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    Medicamentos formulario infantil modelo OMS  2010 Medicamentos formulario infantil modelo OMS 2010 Document Transcript

    • Based on the Second Model List of Essential Medicines for Children 2009 2010
    • WHO Library Cataloguing-in-Publication Data: WHO model formulary for children 2010. Based on the second model list of essential medicines for children 2009. 1.Essential drugs. 2.Formularies. 3.Pharmaceutical preparations. 4.Child. 5.Drug utilization. I.World Health Organization. ISBN 978 92 4 159932 0 (NLM classification: QV 55) © World Health Organization 2010 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
    • Acknowledgements WHO Reviewers: (listed in alphabetical order) Pedro Albajar-Vinas Jorge Alvar Ezquerra Clinical Editors: Siobhan Crowley Siobhan Andrews1, BPharm GradDipPharmPrac Denis Daumerie Noel Cranswick1, 3, MBBS BMedSc FRACP Margriet den Boer Suzanne Hill2, BMed (Hons) PhD GradDipEpi FAFPHM Tarun Dua Brian Lilley1, BPharm GradDipHospPharm MBA Philippe Duclos Leith Lilley1, BPharm MClinPharm Dirk Engels Kate Milner3, MBBS MPH Olivier Fontaine Courtney Munro1, BPharm GradCertPharmPrac Jose Ramon Franco Minguell Christine Plover1, BPharm (Hons) MClinPharm M. Grzemska David Tickell3, MBBS FRACP Jean Jannin Ivo Kocur 1. The Royal Children’s Hospital, Melbourne Jose Martines 2. Department of Essential Medicines and Pharmaceutical Shanthi Mendis Policies, World Health Organization, Geneva Lulu Muhe 3. Centre for International Child Health, Department of Paediatrics, The University of Melbourne Peter Olumese Ana Padilla Marroquin Reviewers: Juan Pena-Rosas Jonathan Akikusa Pere Perez Simarro Chris Barnes Cathy Roth Naor Bar-Zeev Shekhar Saxena Robert Berkowitz Joanna Tempowski Louise Bordun Wilson Were Penelope Bryant Special thanks to Monique Renevier Thomas Connell for organizing the WHO reviews. Nigel Crawford Andrew Daley Publisher: Andrew Davidson MIMS Australia Trevor Duke (UBM Medica Australia Pty Ltd) James Elder Steve Graham Editors: Amy Gray Matthew Bidgood, BPharm (Hons) PhD Adam Jenney Elizabeth Donohoo, BSc GradCertHlthSc Joshua Kausman Niroshni Gunewardhane, MD Julian Kelly Allyson Harvey, RN BA (Hons) DipBEP Stuart Lewena Valerie Hoa, MPharm (ClinPharm) Sarah McNab Sue Hunter, BVSc (Hons) Rob McDougall Sarah Keen, BPharm Jodie McVernon Olivia Wroth, BVSc DipBEP Paul Monagle Anna Moon Production: Anastasia Pellicano Robert Johanson, BAppSc Rob Roseby Karthick Mani, MCompSc Fiona Russell Corrina Rivett Helen Savoia Daniela Velcich Mike Starr Andrew Steer Business: Garry Warne Margaret Gehrig, Keith Waters BHealthSc (Mgt), AssocDipNursing (Mgt), RN Special thanks to Julian Kelly for Helen Gilmour, organizing the expert reviews. BAppSc (Haem) GradDip (Mktg) WHO Model Formulary for Children 2010 iii
    • SELECTED WHO PUBLICATIONS OF RELATED INTEREST The selection and use of essential medicines. Report of the WHO Expert Committee (including the WHO Model List of Essential Medicines and the 2nd WHO Model List of Essential Medicines for Children) WHO Technical Report Series, No. 958, 2010 (in print) Pocket book of hospital care for children. 2005 (378 pages) The international pharmacopoeia, fourth edition. Volume 1: general notices; monographs for pharmaceutical substances (A–O) Volume 2: monographs for pharmaceutical substances (P–Z); monographs for dosage forms and radiopharmaceutical preparations; methods of analysis; reagents. 2006 (1500 pages), also available in CD-ROM version Basic tests for drugs: pharmaceutical substances, medicinal plant materials and dosage forms. 1998 (94 pages) Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Volume 1: 1997 (244 pages) Volume 2: Good manufacturing practices and inspection. 2nd updated edition, 2007 (in print) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. WHO Technical Report Series, No. 953, 2009 (172 pages) International nonproprietary names (INN) for pharmaceutical substances. Cumulative List no. 13 2010 (available in CD-ROM format only) Further information on these and other WHO publications can be obtained from WHO Press, World Health Organization, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int; order on line: http://www.who.int/bookorders) iv WHO Model Formulary for Children 2010
    • Contents Selected WHO Publications of Interest ....................................................................................... iv Abbreviations ............................................................................................................................ vi Introduction ............................................................................................................................ vii Guidance for Prescribing in Paediatrics........................................................................................ viii How to Use the WMFC .............................................................................................................. xii Changes to the WHO Model List of Essential Medicines for Children........................................ xv Section 1: Anaesthetics ......................................................................................................... 2 Section 2: Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) ........................................................................................... 18 Section 3: Antiallergics and medicines used in anaphylaxis ................................................... 27 Section 4: Antidotes and other substances used in poisonings ............................................... 36 Section 5: Anticonvulsants/antiepileptics .............................................................................. 49 Section 6: Anti-infective medicines ....................................................................................... 64 Section 7: Antimigraine medicines........................................................................................ 240 Section 8: Antineoplastic, immunosuppressives and medicines used in palliative care ........... 246 Section 9: Antiparkinsonism medicines ................................................................................ 295 Section 10: Medicines affecting the blood ............................................................................... 297 Section 11: Blood products and plasma substitutes ................................................................. 308 Section 12: Cardiovascular medicines ..................................................................................... 313 Section 13: Dermatological medicines (topical) ...................................................................... 323 Section 14: Diagnostic agents ................................................................................................. 341 Section 15: Disinfectants and antiseptics ................................................................................ 345 Section 16: Diuretics .............................................................................................................. 352 Section 17: Gastrointestinal medicines ................................................................................... 359 Section 18: Hormones, other endocrine medicines and contraceptives ................................... 374 Section 19: Immunologicals.................................................................................................... 387 Section 20: Muscle relaxants (peripherally-acting) and cholinesterase inhibitors ..................... 431 Section 21: Ophthalmological preparations ............................................................................ 438 Section 22: Oxytocics and antioxytocics ................................................................................. 447 Section 23: Peritoneal dialysis solution ................................................................................... 449 Section 24: Psychotherapeutic medicines ................................................................................ 452 Section 25: Medicines acting on the respiratory tract .............................................................. 461 Section 26: Solutions correcting water, electrolyte and acid-base disturbances......................... 467 Section 27: Vitamins and minerals ......................................................................................... 478 Section 28: Ear, nose and throat conditions in children .......................................................... 488 Section 29: Specific medicines for neonatal care...................................................................... 493 Index ............................................................................................................................ 500 WHO Model Formulary for Children 2010 v
    • Abbreviations ACE angiotensin-converting enzyme AIDS acquired immunodeficiency syndrome ALP alkaline phosphatase APTT activated partial thromboplastin time ART antiretroviral ATC anatomical therapeutic chemical AUC area under the curve AV atrioventricular BCG Bacillus Calmette–Guérin (vaccine) BNFC British National Formulary for Children BP British Pharmacopoeia BSA body surface area CNS central nervous system CrCl creatinine clearance CSF cerebrospinal fluid ECG electrocardiogram EEG electroencephalogram EMLc Essential Medicines List for Children G6PD glucose 6-phosphate dehydrogenase GFR glomerular filtration rate GI gastrointestinal GORD gastro-oesophageal reflux disease GVHD graft-versus-host disease HIV human immunodeficiency virus Ht height IM intramuscular INR international normalized ratio IV intravenous MB multibacillary leprosy MDI metered dose inhaler MDR-TB multidrug-resistant tuberculosis MMR measles, mumps, rubella MRI magnetic resonance imaging MSSA methicillin-sensitive Staphylococcus aureus MTCT mother-to-child transmission NSAIM non-steroidal anti-inflammatory medicine ORS oral rehydration solution PB paucibacillary leprosy PCP Pneumocystis carinii (Pneumocystis jiroveci) pneumonia PDA patent ductus arteriosus PR per rectum PTB pulmonary tuberculosis PVC polyvinyl chloride SC subcutaneous SIADH syndrome of inappropriate antidiuretic hormone secretion spp. species SSRI selective serotonin reuptake inhibitor TB tuberculosis TSH thyroid stimulating hormone USP United States Pharmacopeia WHO World Health Organization Wt weight vi WHO Model Formulary for Children 2010
    • Introduction In 2007, the World Health Assembly passed a Resolution titled ‘Better Medicines for Children’. This resolution recognized the need for research and development into medicines for children, including better dosage forms, better evidence and better information about how to ensure that medicines for treating the common childhood diseases are given at the right dose for children of all ages. The World Health Organization has therefore developed a program of work on medicines for children, including the development of a Model List of Essential Medicines for children (EMLc). As an extra resource for health-care workers and national programmes that supply medicines for children, this new edition of the WHO Model Formulary has been prepared, based on the 2nd edition of the EMLc, to provide prescribers with the best information about how to use the medicines included on the List. In developing the WHO Model Formulary for Children, the editors have based decisions on treatment regimens on the best available evidence from clinical studies in children, that have been assessed and evaluated by the WHO Expert Committee on Selection and Use of Essential Medicines. However, as has been found by all authorities in relation to medicines for children, in many cases the recommendations on dose and duration of treatment in children have to be extrapolated from studies in adults and adjusted based on our understanding of the effect of age and development on the absorption, distribution and metabolism and excretion of different medicines in children of different ages. One of the aims of this publication is therefore not only to describe what is known about treatments, but to highlight where more research is needed. An electronic version of the WHO Formulary for Children is also available, intended as a starting point for developing institutional or national formularies. The text of the Formulary can be used by groups who wish to develop their own version, by adapting the text or by adding or deleting entries to align the formulary to their own list of essential medicines. This edition of the WHO Model Formulary is fully compatible with the 2nd List of Essential Medicines for Children, as recommended by the WHO Expert Committee on the Selection and Use of Essential Medicines in March 2009. Comments and suggestions are welcome and should be sent to: The Editor; WHO Model Formulary Medicines Access and Rational Use Department of Essential Medicines and Pharmaceutical Policies World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Email : modelformulary@who.int WHO Model Formulary for Children 2010 vii
    • Factors influencing paediatric drug therapy Medicines in children It was once said that the moral test of government is how that government treats those who are in the dawn of life, the children; those who are in the twilight of life, the elderly; and those who are in the shadows of life—the sick, the needy and the handicapped.1 Children are among the most vulnerable individuals in any society. Nowhere is this more true than in their access to appropriate health care. As part of the treatment of children, health-care workers need access to drug dosage information. This formulary aims to provide that information universally, to assist in the management of children. The use of medicines in infants and children presents a unique set of challenges to the prescriber. Physiological variances between children and adults, including the ontogeny of organ maturity and body composition, significantly influence the actions, effectiveness and safety of medicines. However, most pharmacokinetic and pharmacodynamic studies provide little, if any, information on drug action in infants and children, because they are usually conducted in adults. Paediatric pharmacology developed initially from the extrapolation of therapeutic practice and experience in adults and the use of “scaled down” adult doses. This practice is clinically successful for the majority of drugs which are relatively non-toxic and have a wide margin between therapeutic and toxic doses. Drugs with a narrow therapeutic margin, such as the aminoglycoside antibiotics and digoxin, require more sophisticated knowledge and individualized dosage regimens. Doses of such agents are scaled by weight or allometrically (wt¾), then modified according to the results of serum drug concentration measurements, if these are available. Over the last two decades, there has been an increased recognition of the necessity to perform studies specifically in children and adolescents. Major national and international approaches, such as those of the European Union and the United States, have resulted in some new information to improve the use of medicines in children. This formulary is the result of the establishment of the WHO Model List of Essential Medicines for Children (EMLc). The list can be accessed at http://www.who.int/selection_medicines/en/. Absorption Oral absorption The gastrointestinal tract, particularly the stomach, undergoes significant changes from birth until around 3 years of age. Before then, the stomach has low levels of acid, and acid-labile drugs, such as the penicillins, show enhanced absorption. On the other hand, this depressed level of acidity may result in reduced absorption of weak acids such as phenobarbitone, phenytoin and rifampicin. The incomplete absorption experienced with these anticonvulsants may necessitate their continued parenteral administration. The delayed gastric emptying seen in neonates and young infants is probably not as important as previously believed. In the first few weeks of life this may be significant, but most sick neonates receive their drugs parenterally. viii WHO Model Formulary for Children 2010
    • Of considerable importance, particularly to the general public, is the question of drug administration and absorption relative to meals. Current evidence suggests that, with the exception of isoniazid, captopril, rifampicin, phenoxymethylpenicillin and tetracyclines (except doxycycline and minocycline), all medications should be administered with meals to avoid gastrointestinal irritation and to aid compliance. Topical absorption Topical absorption of drugs is enhanced in children and especially in infants. This is a direct result of the relative thinness of the stratum corneum. Absorption may be further enhanced in the presence of burnt or excoriated areas and with occlusive dressings. This has been well documented with the use of corticosteroid creams for eczema and nappy rash in infants, especially when the area treated has been occluded with plastic pants. Rectal absorption Rectal administration may be useful in patients who are vomiting and in infants and young children who are reluctant to take oral medication. The rectal route is not ideal for all drugs. Considerable individual variation in rectal venous drainage, and hence in the extent of drug absorption, can produce either sub-therapeutic or toxic drug levels. Drugs with narrow therapeutic margins should not be administered rectally. One drug which is recommended for rectal administration in children is diazepam for the treatment of seizures. Paracetamol may also be administered rectally; however, the absorption may be erratic and therapeutic levels cannot be guaranteed. Distribution Numerous factors, including body composition, plasma–protein binding and the blood–brain barrier influence drug distribution in the various paediatric age groups. Body composition Total body water and fat composition alter significantly during the transition from birth to adult life. Total body water as a percentage of body weight is approximately 80% at birth, 65% at 12 months and 60% for a young adult male. On the other hand, fat content as a percentage of body weight varies with age, being about 3% in premature infants, 12% in full-term neonates, 30% at 1 year of age and about 18% in the average adult. Therefore, larger mg/kg body weight doses of water-soluble drugs need to be given to neonates and infants to achieve plasma concentrations similar to those seen in adults. However, this has to be balanced against diminished hepatic function and renal elimination before arriving at a final dosage recommendation. WHO Model Formulary for Children 2010 ix
    • Plasma protein binding Drug–protein binding is diminished in neonates due to a lower concentration of plasma proteins, particularly albumin, and the lower drug-binding capacity of fetal albumin. This may lead to an increase in the fraction of unbound, pharmacologically active drug in the plasma. There may also be competition between endogenous substances, especially free fatty acids and bilirubin, and drugs for albumin-binding sites. However, when drugs administered to neonates are examined in detail, very few highly protein- bound drugs are used. From a practical point of view, highly protein-bound drugs such as phenytoin, sulfonamides, salicylates and diazepam should be given with caution in the presence of hyperbilirubinaemia. In older children, there are several disease states which may affect drug–protein binding, including hepatic disease, nephrotic syndrome, chronic renal failure, cardiac failure and malnutrition. Blood–brain barrier The blood–brain barrier is a permeability barrier between the circulation and the brain cells bathed in cerebrospinal fluid (CSF). The blood–brain barrier is functionally incomplete in the neonate, and certain substances show increased penetration into the brain. One of the most important factors which determine the rate of transport of drugs across the blood–brain barrier is their lipid solubility. This gives rise to increased brain uptake of barbiturates and morphine in infants. As meningitis is a relatively common problem in paediatric practice, the extent to which antimicrobial agents penetrate the CSF is an important consideration. Although some agents penetrate poorly under normal circumstances, in the presence of meningeal inflammation, penetration may be considerably enhanced, so that adequate CSF drug concentrations are attained. Drugs in this category include penicillins, cefalosporins, rifampicin and vancomycin. Drugs which penetrate well even in the absence of meningeal inflammation include chloramphenicol and the combination sulfamethoxazole and trimethoprim. Although the aminoglycosides continue to be used for meningitis caused by Gram-negative organisms, the CSF concentrations achieved are generally low and inconsistent. Higher concentrations can be obtained by direct intrathecal or intraventricular injections, but controversy exists over the efficacy of such routes of administration. The newer cefalosporins, such as cefotaxime, appear to be more appropriate agents in most cases. Metabolism The various metabolic reactions that occur in the mature liver are not fully developed at birth. Cardiac insufficiency and respiratory distress may also contribute to decreased metabolic activity. Lidocaine, phenobarbital, phenytoin and diazepam show decreased metabolism in the neonate, resulting in increased drug half-lives. During the first 15 days of life in premature and full-term babies, decreased metabolism is evident, but this is followed by a dramatic increase. Between 1 and 10 years of age, hepatic microsomal x WHO Model Formulary for Children 2010
    • oxidation is more rapid than in adults. Therefore phenobarbital, phenytoin and theophylline have shorter half-lives in children than in adults. This more rapid metabolism is almost certainly due to the fact that, during childhood, the liver is larger relative to body weight than in adult life. Allometric scaling may give a better prediction of the metabolic activity of the liver. Excretion Renal function is significantly less developed in premature and full-term neonates than it is in children and adults. Adult values for glomerular filtration rate are reached after about 3 to 6 months of age, while tubular function does not mature fully until after this. Renal function is of particular importance to drug disposition in the neonatal period. Most sick neonates receive antibiotics for suspected or proven infection, and most of these agents are water soluble. In general, the lower the gestational age of the infant, the more prolonged the half-life will be in this period. The rate of elimination increases rapidly during the ensuing weeks, so that half-lives similar to those seen in adults are usually achieved by the end of the first month. The WHO Model Formulary for Children The hope is that this Formulary improves therapies in children by offering the best dosing information for those medicines currently listed on the EMLc. The Formulary is not, however, a substitute for the appropriate use of treatment guidelines, and should be used in conjunction with guidelines such as the WHO Pocket Book of Hospital Care for Children. 1. Humphrey, Hubert H. Speech at the dedication of the Hubert H Humphrey building, Washington, DC, 4 November 1977. http://www.vernalproject.org/IcDQuotes/IcDQuoteA.shtml (accessed 30 March 2008). WHO Model Formulary for Children 2010 xi
    • How to use the WHO Model Formulary for Children Medication monographs are listed by section according to the WHO Model List of Essential Medicines for Children March 2009. Omission of a particular medication does not necessarily indicate that it is not available or recommended in children; merely that it is not considered an essential medicine for children by WHO. Medicines and dosage forms are listed in alphabetical order within each section and there is no implication of preference for one form over another. Standard treatment guidelines should be consulted for information on appropriate dosage forms. The WHO Model Formulary for Children classifies children by age and doses medicines accordingly, most often in mg/kg. The Formulary is intended for use for children up to 12 years of age. Definition of age ranges Neonate: 0–28 days Infant 1–12 months Child 1–12 years If a maximum dose is listed this provides an indication of the upper dose limit when dosing paediatrics per kilogram. Allowances must be made when using weight as a basis for dosing in oedematous or obese children. In such children the ideal weight for height and age should be used. In many cases, progressive dose adjustments may be required according to the patient’s response. Doses based on surface area are quoted for some drugs. Surface area is calculated by the following equation: Body surface area (m2) = Ht (cm) x Wt (kg) 3600 Mosteller RD. Simplified calculation of body surface area. New England Journal of Medicine, 1987, 317(17):1098 (letter). Explanatory notes for drug monographs: Section and section number This indicates the section and any subsection that the medicine is classified under as per the WHO Model List of Essential Medicines for Children March 2009. A single medication may appear multiple times on the list in different sections for differing indications. Drug Name The generic (non-proprietary) name. Dose Forms The dose form is listed as per the WHO Model List of Essential Medicines for Children March 2009. Some countries may have access to preparations which differ in terms of concentration or dose form. When a medicine is in solution or a mixture the concentration in the medication monograph is expressed as mg/ml to avoid confusion, this may differ from the WHO Model List of Essential Medicines for Children March 2009. xii WHO Model Formulary for Children 2010
    • ATC Code The Anatomical Therapeutic Chemical (ATC) classification system code designated by WHO to classify drugs. Special Notes Indicate if the medicine is also known by another name, different spelling or abbreviation. Also, notes if there is a WHO age/weight restriction or representative status. Warnings Where there is a significant warning, risk or adverse effect associated with using the medication. Indications Indications for use from the WHO Model List of Essential Medicines for Children March 2009. Contraindications Details of any contraindications to use of the drug. Precautions Details of any precautions or monitoring required. Dose Indication. Route: Age dose and frequency. Alternative route: Age dose and frequency. Renal impairment Advice for use of this drug in these circumstances. Renal impairment is usually divided into three grades: Mild: GFR 20–50 ml/minute or approximate serum creatinine 150–300 micromol/litre Moderate: GFR 10–20 ml/minute or serum creatinine 300–700 micromol/litre Severe: GFR < 10 ml/minute or serum creatinine > 700 micromol/litre Consult specialist texts for further information on use of drugs in renal impairment. Hepatic Impairment Advice for use of this drug in these circumstances. Consult specialist texts for further information on use of drugs in hepatic impairment. Adverse effects Details of adverse effects associated with this medication. Adverse effects have been classified by incidence where possible: Common: > 1% (> 1 in 100 people) Uncommon: 0.1%–1% ( > 1 in 1,000 people and < 1 in 100 people) Rare: < 0.1% (< 1 in 1,000 people) WHO Model Formulary for Children 2010 xiii
    • Interactions with other medications Details any drug interactions. Potentially hazardous drug interactions are indicated by the symbol * meaning the combined administration of the drugs involved should be avoided, or only taken with caution and appropriate monitoring. Interactions with no symbol do not usually have serious consequences. Notes Includes ancillary information where applicable such as administration instructions, patient advice and storage instructions. References Includes a list of references used to compile this drug monograph. Consult individual references for more information. The presence of an entry on the Essential Medicines List and/or WHO Children’s Formulary carries no assurance as to pharmaceutical quality. It is the responsibility of the relevant national or regional drug regulatory authority to ensure that each product is of appropriate pharmaceutical quality (including stability) and that when relevant, different products are interchangeable. For recommendations and advice concerning all aspects of the quality assurance of medicines see the WHO Medicines web site http://www.who.int/medicines/areas/quality_assurance/en/index.html xiv WHO Model Formulary for Children 2010
    • Changes to the WHO Model List of Essential Medicines for Children Changes made to the 1st List (October 2007) to produce the 2nd List (March 2009) are listed below. Changes to the List Additions Section 4.2 Acetylcysteine, oral liquid: 10% and 20%. Section 5 Lorazepam, parenteral formulation: 2 mg/ml in 1 ml ampoule; 4 mg/ml in 1 ml ampoule. Section 6.2.1 Cefalexin, powder for reconstitution with water: 125 mg/5 ml; 250 mg/5 ml and solid oral dosage form: 250 mg. Cefotaxime, powder for injection: 250 mg per vial. Ceftazidime, powder for injection: 1 g (as pentahydrate) in vial. Section 6.2.2 Ciprofloxacin, oral liquid: 250 mg/5 ml and solution for IV infusion: 2 mg/ml. Doxycycline, oral liquid: 25 mg/5 ml and 50 mg/5 ml. Section 6.2.4 Amikacin, powder for injection: 100 mg; 500 mg in vial. Section 6.4.2.3 Atazanavir, solid oral dosage form: 100 mg; 150 mg; 300 mg. Lopinavir + ritonavir (LPV/r), tablet (heat stable): 100 mg + 25 mg ; 200 mg + 50 mg. Ritonavir, tablet (heat stable): 25 mg; 100 mg. Lamivudine + nevirapine + stavudine, tablet (dispersible): 30 mg + 50 mg + 6 mg; 60 mg + 100 mg + 12 mg. Lamivudine + nevirapine + zidovudine, tablet: 30 mg + 50 mg + 60 mg. Lamivudine + zidovudine, tablet: 30 mg + 60 mg. Section 6.5.3.1 Artemether + lumefantrine, tablet (dispersible): 20 mg + 120 mg. Section 6.5.4 Sulfadiazine, tablet: 500 mg. Section 8.2 Carboplatin, injection: 50 mg/5 ml; 150 mg/15 ml; 450 mg/45 ml; 600 mg/60 ml. Section 8.4 Amitriptyline, tablet: 10 mg; 25 mg. Cyclizine, injection: 50 mg/ml and tablet: 50 mg. Dexamethasone, injection: 4 mg/ml and tablet: 2 mg. Diazepam, injection: 5 mg/ml and oral liquid: 2 mg/5 ml and rectal solution: 2.5 mg; 5 mg; 10 mg and tablet: 5 mg; 10 mg. Docusate sodium, capsule: 100 mg and oral liquid: 50 mg/5 ml. Hyoscine hydrobromide, injection: 400 micrograms/ml; 600 micrograms/ml and transdermal patches: 1 mg/72 hours. Ibuprofen, oral liquid: 100 mg/5 ml and tablet: 200 mg; 400 mg and 600 mg. Midazolam, injection: 1 mg/ml and 5 mg/ml. Morphine, granules (modified release) (to mix with water): 20 mg; 30 mg; 60 mg; 100 mg; 200 mg and injection: 10 mg/ml and oral liquid: 10 mg/5 ml and tablet (controlled release): 10 mg; 30 mg; 60 mg and tablet (immediate release): 10 mg. Senna, oral liquid: 7.5 mg/5 ml. WHO Model Formulary for Children 2010 xv
    • Section 12.3 Enalapril, tablet: 2.5 mg; 5 mg. Section 15.1 Chlorhexidine, solution: 20% (digluconate). Section 17 Pancreatic enzymes, age-appropriate formulations and doses including lipase, protease and amylase. Section 17.1 Omeprazole, powder for oral liquid: 20 mg; 40 mg sachets and solid oral dosage form: 10 mg; 20 mg; 40 mg. Section 17.2 Dexamethasone, injection: 4 mg/ml in 1 ml ampoule and oral liquid: 0.5 mg/5 ml; 2 mg/5 ml and solid oral dosage form: 0.5 mg; 0.75 mg; 1.5 mg; 4 mg. Ondansetron, injection: 2 mg base/ml in 2 ml ampoule (as hydrochloride) and oral liquid: 4 mg base/5 ml and solid oral dosage form: Eq 4 mg base; Eq 8 mg base. Section 18.1 Fludrocortisone, tablet: 100 micrograms. Hydrocortisone, tablet: 5 mg; 10 mg; 20 mg. Section 28 Ear, nose and throat conditions in children (new section): Acetic acid, topical: 2%, in alcohol. Budesonide, nasal spray: 100 micrograms per dose. Ciprofloxacin, topical: 0.3% drops. Xylometazoline, nasal spray: 0.05%. Section 29 Specific medicines for neonatal care (new section): Caffeine citrate, injection: 20 mg/ml (equivalent to 10 mg caffeine base/ml) and oral liquid: 20 mg/ml (equivalent to 10 mg caffeine base/ml). Surfactant, suspension for intratracheal instillation: 25 mg/ml or 80 mg/ml. Prostaglandin E, solution for injection: Prostaglandin E: 0.5 mg/ml in alcohol and Prostaglandin E2: 1 mg/ml. Ibuprofen, solution for injection: 5 mg/ml. Amendments to dosage strength and form Section 5 Diazepam, injection: 5 mg/ml in 2 ml ampoule (intravenous or rectal) changed to rectal solution or gel: 5 mg/ml in 0.5 ml; 2 ml and 4 ml tubes. Section 10.2 Heparin sodium, injection: 1000 IU/ml; 5000 IU/ml; 20 000 IU/ml in 1 ml ampoule changed to injection: 1000 IU/ml; 5000 IU/ml in 1 ml ampoule. Section 16 Spironolactone, oral liquid: 1 to 20 mg/ml and tablet: 25 mg changed to oral liquid: 5 mg/5 ml; 10 mg/5 ml; 25 mg/5 ml and tablet: 25 mg. Section 25.1 Budesonide, 50 micrograms per dose (dipropionate); 250 micrograms (dipropi- onate) per dose changed to inhalation (aerosol): 100 micrograms per dose; 200 micrograms per dose. Section 26.2 Potassium chloride, solution: 11.2% in 20 ml ampoule changed to solution for di- lution: 7.5% (equivalent to K+ 1 mmol/ml and Cl- 1 mmol/ml); 15% (equivalent to K+ 2 mmol/ml and Cl- 2 mmol/ml). xvi WHO Model Formulary for Children 2010
    • Deletions Section 6.2.2 Erythromycin, powder for injection: 500 mg (as lactobionate) in vial. Sulfadiazine, injection: 250 mg (sodium salt) in 4 ml ampoule and tablet: 500 mg. Section 6.2.4 Rifampicin + isoniazid, tablet: 60 mg + 30 mg; 60 mg + 60 mg (for intermittent use three times weekly). Rifampicin + isoniazid + pyrazinamide, tablet: 60 mg + 30 mg + 150 mg. Section 6.4.2.3 Nelfinavir (NFV), oral powder: 50 mg/g and tablet: 250 mg (as mesilate). Section 8.2 Cisplatin, powder for injection: 10 mg; 50 mg in vial. Section 13.5 Dithranol, ointment: 0.1% to 2.0%. Section 17.2 Promethazine, injection: 25 mg (hydrochloride)/ml in 2 ml ampoule and oral liquid: 5 mg (hydrochloride)/5 ml and tablet: 10 mg; 25 mg (hydrochloride). Section 18.5 Insulin injection (soluble), injection: 40 IU/ml in 10 ml vial. Intermediate-acting insulin, injection: 40 IU/ml in 10 ml vial (as compound insulin zinc suspension or isophane insulin). Section 25.2 Caffeine citrate, injection: 20 mg/ml (equivalent to 10 mg caffeine base/ml) and oral liquid: 20 mg/ml (equivalent to 10 mg caffeine base/ml). Section 26.2 Glucose with sodium chloride, 4% glucose, 0.18% sodium chloride (equivalent to Na+ 30 mmol/l, Cl- 30 mmol/l). Potassium chloride, solution: 11.2% in 20 ml ampoule. Moved from complementary to core Section 6.5.2 Amphotericin B, powder for injection: 50 mg in vial. As deoxycholate or liposomal. WHO Model Formulary for Children 2010 xvii
    • xviii WHO Model Formulary for Children 2010
    • SECTION 1: Anaesthetics 1.1 General anaesthetics and oxygen.................................................. 2 1.2 Local anaesthetics ........................................................................ 8 1.3 Preoperative medication and sedation for short-term procedures................................................................ 13 WHO Model Formulary for Children 2010 1
    • 1 Anaesthetics 1 Anaesthetics 1.1 General anaesthetics and oxygen To produce a state of prolonged full surgical anaesthesia reliably and safely, careful administration of a variety of drugs and close monitoring of the patient are required. Anaesthesia should be undertaken by non-specialist personnel only as a last resort, because anaesthetic drugs may be fatal if inappro- priately used. Irrespective of the type of anaesthesia used (i.e. general or regional), it is essential that facilities for intubation and mechanically assisted ventilation are available. Anaesthesia may be induced and maintained with intravenous medications and/or inhalation of a volatile agent (section 1.1). A range of other drugs including local anaesthetics (section 1.2), pre- operative medications (section 1.3), opioid analgesics (section 2.2), muscle relaxants and reversal agents (e.g. cholinesterase inhibitors; section 20) may also be required. Oxygen should be added routinely during anaesthesia with inhalation agents, even when air is used as the carrier, to protect against hypoxia. Halothane ATC code: N01AB01 Inhalation Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Induction and maintenance of anaesthesia. Contraindications: History of unexplained jaundice or fever following previous exposure to halothane; family history of malignant hyperthermia; raised cerebrospinal fluid pressure; porphyria. Precautions: Anaesthetic history should be carefully taken to determine previous exposure and previous reactions to halothane (fulminant hepatic failure is a rare complication of re-exposure to halothane); avoid use if adequate resuscitation facilities are not available. Dose: Induction of anaesthesia. Inhalation through specifically calibrated vaporizer: Infant or Child initially 0.5% then gradually increase inspired gas concentration to 1.5–2% in oxygen or nitrous oxide-oxygen. Maintenance of anaesthesia. Inhalation through specifically calibrated vaporizer: Infant or Child 0.5–2% in oxygen or nitrous oxide-oxygen. Hepatic impairment: Avoid if history of unexplained pyrexia or jaundice following previous exposure to halothane. Adverse effects: Common Bradycardia, respiratory depression. Uncommon Arrhythmias, hepatitis (may be fatal). 2 WHO Model Formulary for Children 2010
    • 1.1 General anaesthetics and oxygen Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Epinephrine (adrenaline): risk of arrhythmias. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. * Levodopa: risk of arrhythmias. Spironolactone: enhanced hypotensive effect. Suxamethonium: enhanced effects of suxamethonium. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Vecuronium: enhanced effects of vecuronium. * Verapamil: enhanced hypotensive effect and AV delay. Notes: Preferred drug if intubation is likely to be difficult. Does not augment salivary or bronchial secretions. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ketamine ATC code: N01AX03 Injection: 50 mg (as hydrochloride)/ml in 10 ml vial Indications: Induction and maintenance of anaesthesia; analgesia for painful procedures of short duration. Contraindications: Thyrotoxicosis; hypertension; severe cardiac disease; history of cerebrovascular accident, cerebral trauma, intracerebral mass or haemorrhage or other cause of raised intracranial pressure; eye injury and increased intraocular pressure; psychiatric disorders, particularly hallucinations; porphyria. Precautions: Increased cerebrospinal fluid pressure; predisposition to hallucinations or nightmares; supplementary analgesia often required in surgical procedures involving visceral pain pathways (morphine may be used but addition of nitrous oxide will often suffice); administer an antisialogogue to prevent excessive salivation leading to respiratory difficulties; during recovery, patient must remain undisturbed but under observation. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 3
    • 1 Anaesthetics Dose: Titrate dose to effect. Induction and maintenance of anaesthesia (short procedures), analgesia for short painful procedures. Intravenous injection over at least 60 seconds: Neonate, Infant or Child 1–2 mg/kg produces 5–10 minutes of surgical anaesthesia, adjusted according to response. Intramuscular injection: Neonate 4 mg/kg for 15 minutes of surgical anaesthesia (adjusted according to response). Infant or Child 4–13 mg/kg (4 mg/kg sufficient for some diagnostic procedures), adjusted according to response; 10 mg/kg usually produces 12–25 minutes of surgical anaesthesia. Induction and maintenance of anaesthesia (longer procedures). Continuous intravenous infusion: Neonate initially 0.5–2 mg/kg followed by a continuous intravenous infusion of 500 micrograms/kg/hour adjusted according to response; up to 2 mg/kg/hour may be used to produce deep anaesthesia. Infant or Child initially 0.5–2 mg/kg followed by a continuous intravenous infusion of 0.6–2.7 mg/kg/hour adjusted according to response. Adverse effects: Common Raised blood pressure and pulse rate, raised intracranial pressure, raised intraocular pressure, hypersalivation, increased muscle tone, emergence reactions including hallucinations, restlessness, confusion, irrational behaviour. Uncommon Hypotension, bradycardia. Rare Arrhythmias. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. Spironolactone: enhanced hypotensive effect. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: For IV injection, dilute to a concentration of no more than 50 mg/ml with glucose 5% or sodium chloride 0.9% or water for injection. For continuous IV infusion, dilute to a concentration of 1 mg/ml with glucose 5% or sodium chloride 0.9%; use microdrip infusion for maintenance of anaesthesia. Premedication with an anticholinergic to reduce secretions is recommended before its use in anaesthesia. Anaesthesia persists for up to 15 minutes after a single intravenous injection and is characterized by profound analgesia. Subanaesthetic doses may be used to provide analgesia and sedation for painful procedures of short duration (e.g. dressing of burns, radiotherapeutic procedures, marrow sampling and minor orthopaedic procedures). Recovery is relatively slow and associated with a high incidence of hallucinations and other emergence reactions, such as delirium. 4 WHO Model Formulary for Children 2010
    • 1.1 General anaesthetics and oxygen References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Nitrous oxide ATC code: N01AX13 Inhalation Indications: Maintenance of anaesthesia in combination with other anaesthetic agents and muscle relaxants; analgesia for emergency management of injuries, during postoperative physiotherapy and for refractory pain in terminal illness. Contraindications: Demonstrable collection of air in pleural (pneumothorax), pericardial or peritoneal space; intestinal obstruction; occlusion of middle ear; arterial air embolism; decompression sickness; chronic obstructive airway disease; emphysema. Precautions: Minimize exposure of staff; vitamin B12 deficiency. Dose: Maintenance of light anaesthesia. Inhalation using suitable anaesthetic apparatus: Neonate, Infant or Child up to 66% in oxygen. Analgesia. Inhalation using suitable anaesthetic apparatus: Neonate, Infant or Child up to 50% in oxygen, according to the child’s needs. Adverse effects: Common Nausea and vomiting. Uncommon Arrhythmias. Rare Malignant hyperthermia, after prolonged administration: megaloblastic anaemia, leukopenia, agranulocytosis, neuropathy and myeloneuropathy. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. * Methotrexate: increased antifolate effect (avoid concomitant use). Spironolactone: enhanced hypotensive effect. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: Should not be used as a sole anaesthetic agent due to lack of potency. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 5
    • 1 Anaesthetics Oxygen ATC code: V03AN01 Inhalation (medicinal gas) Fire hazard. Avoid use of cautery when oxygen is used with ether; reducing valves on oxygen cylinders must not be greased (risk of explosion). Special Notes: Inhalation gas. Indications: Maintain adequate tissue oxygenation in inhalational anaesthesia and other indications for use in neonates and children. Used during resuscitation and in the treatment of respiratory problems requiring supplemental oxygen. Dose: Concentration of oxygen in inspired anaesthetic gases should never be less than 21%, and preferably 30% or above. The concentration required depends on the condition being treated. Renal impairment: No dosage adjustment necessary. Hepatic impairment: No dosage adjustment necessary. Adverse effects: Long-term use of concentrations greater than 80% have a toxic effect on the lungs leading to pulmonary congestion, exudation and atelectasis. Short-term use of 100% is not associated with these toxic effects. The concentration required depends on the condition being treated; if available, monitoring of the oxygen delivered is strongly recommended, as inappropriate concentration may have serious or even lethal effects. Risks include morbidity, brain damage, and especially in pre-term neonates can cause retinopathy with blindness and chronic lung disease. Use of 100% oxygen should not be withheld in an emergency situation. Interactions with other medicines (* indicates severe): * Bleomycin: serious pulmonary toxicity in patients exposed to conventional oxygen concentrations during anaesthesia. Notes: Monitoring of oxygen delivered is strongly recommended. If available, use oxygen analyser to monitor inspired oxygen and pulse oximeter to monitor oxygen saturation. Oxygen should be added routinely during anaesthesia with inhalational agents, even when air is used as the carrier gas, to protect against hypoxia. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Thiopental ATC code: N01AF03 Powder for injection: 0.5 g; 1 g (sodium salt) in ampoule Special Notes: Specialist skills required for administration and supportive management. Indications: Induction of anaesthesia prior to administration of inhalational anaesthetic; anaesthesia of short duration. Contraindications: Inability to maintain airway; hypersensitivity to barbiturates; severe cardiovascular disease; dyspnoea or obstructive respiratory disease; porphyria. 6 WHO Model Formulary for Children 2010
    • 1.1 General anaesthetics and oxygen Precautions: Asthma; hypotension; cardiovascular disease; myotonic dystrophy; reconstituted solution is highly alkaline: extravasation can result in extensive tissue necrosis and sloughing; intra- arterial injection causes intense pain and may result in arteriospasm; rapid administration may result in severe hypotension and hiccups; renal impairment; hepatic impairment. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Titrate dose to effect. Induction of anaesthesia, anaesthesia of short duration (< 15–20 minutes). Slow IV injection usually as a 2.5% (25 mg/ml) solution over 10–15 seconds: Neonate initially up to 2 mg/kg, then 1 mg/kg repeated as necessary (maximum total dose 4 mg/kg). Infant or Child initially up to 5 mg/kg, then 1 mg/kg repeated as necessary (maximum total dose 7 mg/kg). Renal impairment: May need to reduce dose in severe impairment; administer slowly. Hepatic impairment: Reduce dose for induction in severe liver disease. Adverse effects: Common Hypotension, transient erythema, injection site reactions, cardiorespiratory depression, myocardial depression, prolonged somnolence and recovery, cough, sneezing, cardiac arrhythmias. Uncommon Laryngospasm, rash, allergic reactions. Rare Anaphylaxis, bronchospasm, haemolytic anaemia. Interactions with other medicines (* indicates severe): Amitriptyline: increased risk of arrhythmias and hypotension. * Chlorpromazine: enhanced hypotensive effect. Diazepam: enhanced sedative effect. Enalapril: enhanced hypotensive effect. * Fluphenazine: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. * Haloperidol: enhanced hypotensive effect. Isoniazid: possible potentiation of isoniazid hepatotoxicity. Silver sulfadiazine: enhanced effects of thiopental. Spironolactone: enhanced hypotensive effect. Sulfadiazine: enhanced effects of thiopental. Sulfadoxine + pyrimethamine: enhanced effects of thiopental. Sulfamethoxazole + trimethoprim: enhanced effects of thiopental. Vancomycin: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. * Verapamil: enhanced hypotensive effect and AV delay. Notes: For intravenous injection, dilute to a concentration of 25 mg/ml with water for injection; give over at least 10–15 seconds. Avoid rapid IV injection (may cause hypotension or decreased cardiac output). Induction is rapid and excitement does not usually occur. Thiopental does not have analgesic properties. Monitoring for hypotension and respiratory compromise is required. Lower doses are needed in shock and low cardiac output states. Repeated doses have a cumulative effect especially in neonates where recovery is slower. WHO Model Formulary for Children 2010 7
    • 1 Anaesthetics References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 1.2 Local anaesthetics Drugs used for conduction anaesthesia (also termed local or regional anaesthesia) reversibly block conduction along nerve fibres. Local anaesthetics have variable properties and a range of uses. These include topical (surface) anaesthesia, local anaesthesia and more specialized anaesthetic procedures requiring higher level technical skills (e.g. nerve blocks and regional, epidural and spinal anaesthesia). Local anaesthetic toxicity Local anaesthetic toxicity is usually due to excessively high plasma concentrations. Therefore, great care should be taken to avoid accidental intravascular injection or unwanted systemic absorption. Facilities for resuscitation should be available at all times. Bupivacaine ATC code: N01BB01 Injection: 0.25%; 0.5% (hydrochloride) in vial Injection for spinal anaesthesia: 0.5% (hydrochloride) in 4 ml ampoule to be mixed with 7.5% glucose solution Special Notes: Bupivacaine is a representative local anaesthetic. Various drugs can serve as alternatives. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Infiltration anaesthesia; peripheral and sympathetic nerve block; spinal or epidural anaesthesia (except in dehydrated or hypovolaemic patients); post-operative analgesia. Contraindications: Local inflammation or infection; septicaemia; intravenous regional anaesthesia (e.g. Bier’s block); use in intravenous infusions; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. Precautions: Respiratory impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis. 8 WHO Model Formulary for Children 2010
    • 1.2 Local anaesthetics Dose: Dose needs to be adjusted according to child’s physical status and nature of procedure. Do not use solutions containing preservatives for spinal, epidural or caudal anaesthesia. Local infiltration. 0.5–2.5 mg/kg as a 0.25% or 0.5% solution; maximum dose 1 ml/kg of 0.25% solution, 0.5 ml/kg of 0.5% solution (2.5 mg/kg). Peripheral nerve block. 0.3–2.5 mg/kg as a 0.25% or 0.5% solution; maximum dose 1 ml/kg of 0.25% solution, 0.5 ml/kg of 0.5% solution. epidural block in surgery, using 0.5% preservative free solution. 1–2.5 mg/kg. Caudal block in surgery, using 0.5% preservative free solution. 1–2.5 mg/kg. NOTe Use lower doses for debilitated patients, or in epilepsy or acute illness. Renal impairment: No dosage adjustment necessary. Hepatic impairment: Avoid (or reduce dose) in severe liver disease. Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions, respiratory failure. Interactions with other medicines (* indicates severe): Lidocaine: increased myocardial depression (interaction less likely when lidocaine used topically). Procainamide: increased myocardial depression. * Propranolol: increased risk of bupivacaine toxicity. Quinidine: increased myocardial depression. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 9
    • 1 Anaesthetics Lidocaine ATC code: N01BB02 Injection: 1%; 2% (hydrochloride) in vial Injection for spinal anaesthesia: 5% (hydrochloride) in 2 ml ampoule to be mixed with 7.5% glucose solution Topical forms: 2% to 4% (hydrochloride) Special Notes: Lidocaine is a representative local anaesthetic. Various drugs can serve as alternatives. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Local anaesthetic blocks, dental work and spinal anaesthesia. Contraindications: Local inflammation or infection; septicaemia; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. Precautions: Bradycardia, impaired cardiac conduction; severe shock; respiratory impairment; renal impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis. Dose: Dose needs to be adjusted according to child’s physical status and nature of procedure. Use the lowest effective dose and concentration. Do not use solutions containing preservatives for spinal, epidural, caudal or intravenous regional anaesthesia. Local infiltration and peripheral nerve block, using 1% or 2% solution. Child up to 3 mg/kg (0.3 ml/kg of 1% solution and 0.15 ml/kg of 2% solution; maximum dose 200 mg), not repeated within 2 hours. Surface anaesthesia of pharynx, larynx, trachea, using 4% topical solution. Child up to 3 mg/kg (0.075 ml/kg), not repeated within 2 hours. Instil using a jet spray or apply with a swab. Surface anaesthesia of urethra, using 4% topical solution. Child up to 3 mg/kg (0.075 ml/kg), not repeated within 2 hours. Spinal anaesthesia, using 5% solution (with glucose 7.5%). Child up to 3 mg/kg (0.06 ml/kg), not repeated within 2 hours. Renal impairment: Severe: use with caution. Hepatic impairment: Avoid (or reduce dose) in severe liver disease. Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions and respiratory failure. Interactions with other medicines (* indicates severe): NOTe Interactions less likely when lidocaine is used topically. * Acetazolamide: hypokalaemia caused by acetazolamide antagonizes action of lidocaine. 10 WHO Model Formulary for Children 2010
    • 1.2 Local anaesthetics * Atenolol: increased myocardial depression. Bupivacaine: increased myocardial depression. * Furosemide: action of lidocaine antagonized by hypokalaemia caused by furosemide. * Hydrochlorothiazide: action of lidocaine antagonized by hypokalaemia caused by hydrochlorothiazide. Lopinavir: possibly increased plasma concentration of lidocaine. * Procainamide: increased myocardial depression. * Propranolol: increased myocardial depression; increased risk of lidocaine toxicity. * Quinidine: increased myocardial depression. Suxamethonium: neuromuscular blockade enhanced and prolonged. * Timolol: increased myocardial depression. * Verapamil: increased myocardial depression. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Lidocaine + Epinephrine (Adrenaline) ATC code: N01BB52 Dental cartridge: 2% (hydrochloride) + epinephrine 1:80 000 Injection: 1%; 2% (hydrochloride) + epinephrine 1:200 000 in vial Special Notes: Do not use in digits and appendages, such as fingers, toes, ears, nose and penis, due to risk of ischaemic necrosis. Mainly used for dental anaesthesia. Indications: Dental anaesthesia; infiltration anaesthesia; peripheral nerve block. Contraindications: LIDOCAINe Local inflammation or infection; septicaemia; spinal or epidural anaesthesia in patients taking anticoagulant therapy or with coagulation disorders; severe anaemia or heart disease; spinal or epidural anaesthesia in dehydrated or hypovolaemic patients; hypersensitivity to amide local anaesthetics. ePINePHRINe Cerebral arteriosclerosis; hypersensitivity to sympathomimetic amines. Precautions: LIDOCAINe Bradycardia; impaired cardiac conduction; severe shock; respiratory impairment; renal impairment; hepatic impairment; epilepsy; porphyria; myasthenia gravis; avoid for ring block of digits or appendages (risk of ischaemic necrosis). ePINePHRINe Hypertension; heart block; heart disease; arrhythmias; cerebrovascular disease; thyroid disease; diabetes mellitus. Dose: Child all ages dose needs to be adjusted according to child’s physical status and nature of procedure. Use the lowest effective dose and concentration. Do not repeat the dose within 2 hours. Maximum dose of lidocaine with epinephrine is 7 mg/kg/dose. Renal impairment: LIDOCAINe Severe: use with caution. Hepatic impairment: LIDOCAINe Avoid (or reduce dose) in severe liver disease. WHO Model Formulary for Children 2010 11
    • 1 Anaesthetics Adverse effects: Adverse effects generally occur only with excessive dosage or following intravascular injection. Common Hypotension, bradycardia, lightheadedness, dizziness, blurred vision, restlessness, tremors, confusion, headache, paraesthesia, somnolence, constipation, nausea, vomiting, oedema, erythema at injection site, petechiae, skin irritation. Uncommon Seizures, arrhythmias. Rare Heart block, cardiac arrest, hypersensitivity reactions, respiratory failure. Interactions with other medicines (* indicates severe): LIDOCAINe NOTe Interactions less likely when lidocaine is used topically. * Acetazolamide: hypokalaemia caused by acetazolamide antagonizes action of lidocaine. * Atenolol: increased myocardial depression. Bupivacaine: increased myocardial depression. * Furosemide: action of lidocaine antagonized by hypokalaemia caused by furosemide. * Hydrochlorothiazide: action of lidocaine antagonized by hypokalaemia caused by hydrochlorothiazide. Lopinavir: possibly increased plasma concentration of lidocaine. * Procainamide: increased myocardial depression. * Propranolol: increased myocardial depression; increased risk of lidocaine toxicity. * Quinidine: increased myocardial depression. Suxamethonium: neuromuscular blockade enhanced and prolonged. * Timolol: increased myocardial depression. * Verapamil: increased myocardial depression. Notes: Do not administer intravenously or intra-arterially. Before injecting for local anaesthesia, withdraw syringe plunger to make sure that injection is not into a vein or artery. Use preservative free solutions for epidural or caudal use. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 12 WHO Model Formulary for Children 2010
    • 1.3 Preoperative medication and sedation for short-term procedures 1.3 Preoperative medication and sedation for short- term procedures Appropriate premedication is an important consideration for procedures in children requiring conduction or general anaesthesia. Premedication may be used to help manage pain and anxiety and to improve the course of subsequent anaesthesia. A potent analgesic such as morphine (section 2.2) should be administered peri-operatively to patients in severe pain or for analgesia during and after surgery. Atropine ATC code: A03BA01 Injection: 1 mg (as sulfate) in 1 ml ampoule Indications: Preoperative medication to inhibit salivation and secretions; reversal of the muscarinic effects of cholinergic agents such as neostigmine and pyridostigmine; treatment of bradycardia secondary to cholinergic stimulation. Contraindications: Closed-angle glaucoma; myasthenia gravis; prostatic enlargement; severe gastrointestinal inflammatory disease; gastrointestinal obstruction. Precautions: Down syndrome; children; ulcerative colitis; diarrhoea; heart failure; gastrointestinal disorders; hyperthyroidism; cardiac disorders; tachycardia; hypertension; hypoxia; fever and in warm environments (monitor temperature and keep patients cool); constipation; delirium. CHILDReN Children are at increased risk for rapid rise in body temperature due to suppression of sweat gland activity. Large doses may cause paradoxical hyperexcitability. DOWN SyNDROMe Down syndrome children have both increased sensitivity to cardiac effects and mydriasis. Children with Down syndrome also have more secretions and may require atropine more frequently. Dose: Premedication. IV: Child all ages 20 micrograms/kg (max 600 micrograms) immediately before induction of anaesthesia. SC: Neonate 10–15 micrograms/kg 30–60 minutes before induction of anaesthesia. Infant or Child 20 micrograms/kg (minimum dose 100 micrograms, maximum dose 600 micrograms) 30–60 minutes before induction of anaesthesia. IM: Infant or Child 20 micrograms/kg (minimum dose 100 micrograms, maximum dose 600 micrograms) 30–60 minutes before induction of anaesthesia. Reversal of the muscarinic effects of cholinergic agents. IV: Neonate 20 micrograms/kg. Infant or Child 20 micrograms/kg (maximum dose 600 micrograms). Treatment of bradycardia secondary to cholinergic stimulation. IV: Neonate 20 micrograms/kg. Infant or Child 10–20 micrograms/kg (maximum dose 600 micrograms). Renal impairment: Use with caution. No dose adjustment necessary. Hepatic impairment: Use with caution. No dose adjustment necessary. WHO Model Formulary for Children 2010 13
    • 1 Anaesthetics Adverse effects: Common Dry mouth, blurred vision, photophobia, flushing and dryness of skin, rash, difficulty in micturition, constipation, arrhythmias, tachycardia, palpitations, fever. Uncommon Nausea, vomiting, confusion. Rare Closed-angle glaucoma, seizures. Interactions with other medicines (* indicates severe): NOTe Many drugs have antimuscarinic effects; concomitant use of two or more such drugs can increase adverse effects such as dry mouth, urine retention and constipation. Amitriptyline: increased antimuscarinic adverse effects. Chlorphenamine: increased antimuscarinic adverse effects. Chlorpromazine: increased antimuscarinic adverse effects (but reduced plasma chlorpromazine concentration). Haloperidol: possibly reduced effects of haloperidol. Metoclopramide: antagonism of effects of metoclopramide on gastrointestinal activity. Neostigmine: antagonism of effects of neostigmine. Late unopposed bradycardia may result. Pyridostigmine: antagonism of effects of pyridostigmine. Notes: For IV administration, administer undiluted by rapid IV injection; slow injection may result in paradoxical bradycardia. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Diazepam ATC code: N05BA01 Injection: 5 mg/ml in 2 ml ampoule Tablet: 5 mg Special Notes: Drug subject to international control under the Convention on Psychotropic Substances (1971). Diazepam is a representative benzodiazepine. Various drugs can serve as alternatives. Intravenous diazepam can cause airway obstruction and hypoxia in exactly the same way as any other intravenous anaesthetic. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Premedication before major or minor surgery (for use in short-term procedures); sedation with amnesia for endoscopic procedures and surgery under local anaesthetic. Contraindications: Central nervous system depression or coma; shock; respiratory depression; acute pulmonary insufficiency; sleep apnoea; severe hepatic impairment; marked neuromuscular respiratory weakness including unstable myasthenia gravis. Precautions: Respiratory disease; muscle weakness and myasthenia gravis; marked personality disorder; hepatic impairment; renal failure; close observation required until full recovery after sedation; porphyria. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. 14 WHO Model Formulary for Children 2010
    • 1.3 Preoperative medication and sedation for short-term procedures Dose: Premedication and sedation for clinical procedures. Oral: Infant or Child 200–300 micrograms/kg (maximum 10 mg) 45–60 minutes prior to procedure. Slow IV (over 2–5 minutes): Infant or Child 100–200 micrograms/kg (maximum 5 mg) immediately before procedure. Renal impairment: Severe: start with small doses; increased cerebral sensitivity. Hepatic impairment: Can precipitate coma. Reduce dose by half. Low doses could be used but a shorter acting agent would be preferable. Adverse effects: Common Drowsiness, sedation, confusion, amnesia, muscle weakness, ataxia, slurred speech, pain on intravenous injection. Uncommon Respiratory depression, hypotension, paradoxical insomnia, excitability, hallucinations and aggression, injection pain and thrombophlebitis. Rare Blood dyscrasias including neutropenia, agranulocytosis, anaemia, leukopenia and thrombocytopenia. Interactions with other medicines (* indicates severe): Amitriptyline: enhanced sedative effect. Chlorphenamine: enhanced sedative effect. Chlorpromazine: enhanced sedative effect. Codeine: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. Haloperidol: enhanced sedative effect. Halothane: enhanced sedative effect. Isoniazid: metabolism of diazepam inhibited. Ketamine: enhanced sedative effect. Morphine: enhanced sedative effect. Nitrous oxide: enhanced sedative effect. Phenytoin: plasma phenytoin concentrations possibly increased or decreased by diazepam. Rifampicin: metabolism of diazepam accelerated (reduced plasma concentration). * Ritonavir: plasma concentration possibly increased by ritonavir (risk of extreme sedation and respiratory depression; avoid concomitant use). Spironolactone: enhanced hypotensive effect. Thiopental: enhanced sedative effect. Notes: Do not use via intramuscular injection as absorption is slow and erratic; route should only be used if oral or intravenous administration not possible. Slow intravenous injection into large vein reduces risk of thrombophlebitis. Resuscitation equipment must be available. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 15
    • 1 Anaesthetics Morphine ATC code: N02AA01 Injection: 10 mg (as sulfate or hydrochloride) in 1 ml ampoule Special Notes: Risk of ten times overdose in small children. extreme care required with dose calculation and preparation. Drug subject to international control under the Single Convention on Narcotic Drugs (1961). Indications: Preoperative sedative and analgesic. Contraindications: Respiratory depression; severe respiratory disease; CNS depression; risk of paralytic ileus; raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment); avoid injection in phaeochromocytoma. Precautions: Renal impairment; hepatic impairment; dependence (severe withdrawal symptoms if withdrawn abruptly); hypothyroidism; convulsive disorders; decreased respiratory reserve and acute asthma; hypotension; prostatic hypertrophy; overdosage. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Sedation and analgesia for procedures. IV: Infant or Child 0.05–0.1 mg/kg 5 minutes before the procedure. Maximum dose 15 mg. IM: Infant or Child 0.1 mg/kg 20 minutes before the procedure. Maximum dose 15 mg. Only use IM route for premedication if patient has no IV access and there is adequate respiratory monitoring available. Renal impairment: Moderate to severe: reduce dose or avoid; increased and prolonged effect; increased cerebral sensitivity. Hepatic impairment: Avoid or reduce dose; may precipitate coma. Adverse effects: Common Nausea, vomiting, constipation, lightheadedness, dizziness, sedation, sweating, dysphoria, euphoria, dry mouth, anorexia, spasm of urinary and biliary tract, pruritus, rash, postural hypotension, miosis. Uncommon Respiratory depression (dose related), bradycardia, tachycardia, palpitations. Rare Syndrome of inappropriate antidiuretic hormone secretion (SIADH), anaphylaxis. Interactions with other medicines (* indicates severe): Amitriptyline: possibly increased sedation. Chlorpromazine: enhanced sedative and hypotensive effect. Ciprofloxacin: avoid premedication with morphine (reduced plasma ciprofloxacin concentration) when ciprofloxacin used for surgical prophylaxis. Diazepam: enhanced sedative effect. Haloperidol: enhanced sedative and hypotensive effect. Metoclopramide: antagonism of effect of metoclopramide on gastrointestinal activity. * Ritonavir: possibly increases plasma concentration of morphine. Notes: For intravenous administration, administer slowly over 5 minutes. Risk of ten times overdose in small children. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 16 WHO Model Formulary for Children 2010
    • SECTION 2: Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs).................................................................... 18 2.2 Opioid analgesics ........................................................................ 22 2.3 Medicines used to treat gout ........................................................ 25 2.4 Disease modifying agents used in rheumatoid disorders (DMARDs) .................................................................. 25 WHO Model Formulary for Children 2010 17
    • 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs 2 Analgesics, antipyretics, non-steroidal anti-inflammatory medicines (NSAIMs), medicines used to treat gout and disease modifying agents in rheumatoid disorders (DMARDs) Pain management in children In general terms, principles for drug management of pain in children follow the WHO Analgesic Ladder with the following recommendations for increasing pain: • mild pain: non-opioid with or without non-steroidal anti-inflammatory medicine (NSAIM) and adjuvant • moderate pain: mild opioid with non-opioid, NSAIM and adjuvant • severe pain: strong opioid with non-opioid, NSAIM and adjuvant, with or without specialist techniques. Non-drug strategies are also an important part of managing pain in children. 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Non-opioid analgesics include paracetamol and NSAIMs (section 2.1). These are particularly suitable for musculoskeletal pain. Combining a non-opioid with an opioid analgesic can provide more effective analgesia than either medication alone. Ibuprofen ATC code: M01Ae01 Tablet: 200 mg; 400 mg Special Notes: WHO age/weight restriction: > 3 months. Indications: Mild to moderate pain. Contraindications: Hypersensitivity (including asthma, angioedema, urticaria or rhinitis) to acetylsalicylic acid or any other NSAIM; active peptic ulceration or upper gastrointestinal bleeding; severe renal failure, hepatic failure or cardiac failure. Precautions: Asthma; cardiac disease; volume depletion, such as in gastroenteritis or dehydration (increased risk of renal impairment); concomitant use of drugs that increase risk of bleeding; previous peptic ulceration; coagulation defects; allergic disorders; renal impairment; hepatic impairment. Dose: Mild to moderate pain. Oral: Infant or Child over 3 months 5–10 mg/kg three or four times daily with or after food. Maximum daily dose is 40 mg/kg/day. 18 WHO Model Formulary for Children 2010
    • 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Renal impairment: Mild: use lowest effective dose and monitor renal function; sodium and water retention may occur as may deterioration in renal function possibly leading to renal failure. Moderate to severe: avoid. Hepatic impairment: Use with caution: increased risk of gastrointestinal bleeding and can cause fluid retention; avoid in severe liver disease. Adverse effects: Common Nausea, diarrhoea, dyspepsia, headache, dizziness, fluid retention, raised blood pressure, gastrointestinal ulceration and bleeding. Uncommon Rash, urticaria, photosensitivity, renal impairment. Rare Angioedema, bronchospasm, hepatic damage, alveolitis, pulmonary eosinophilia, pancreatitis, visual disturbances, erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), colitis, aseptic meningitis. Interactions with other medicines (* indicates severe): * Acetylsalicylic acid: avoid concomitant use (increased adverse effects). * Ciclosporin: increased risk of nephrotoxicity. Dexamethasone: increased risk of gastrointestinal bleeding and ulceration. Digoxin: possibly exacerbation of heart failure, reduced renal function and increased plasma digoxin concentration. Enalapril: antagonism of hypotensive effect, increased risk of renal impairment. * Fluoxetine: increased risk of bleeding. Furosemide: risk of nephrotoxicity of ibuprofen increased; antagonism of diuretic effect. Heparin: possibly increased risk of bleeding. Hydrocortisone: increased risk of gastrointestinal bleeding and ulceration. * Levofloxacin: possibly increased risk of convulsions. * Lithium: reduced excretion of lithium (increased risk of toxicity). * Methotrexate: excretion of methotrexate reduced (increased risk of toxicity). * Ofloxacin: possible increased risk of convulsions. Penicillamine: possible increased risk of nephrotoxicity. * Phenytoin: effect of phenytoin possibly enhanced. Prednisolone: increased risk of gastrointestinal bleeding and ulceration. Propranolol: antagonism of hypotensive effect. Ritonavir: plasma concentration possibly increased by ritonavir. Spironolactone: risk of nephrotoxicity of ibuprofen increased; antagonism of diuretic effect; possibly increased risk of hyperkalaemia. * Warfarin: anticoagulant effect possibly enhanced. Zidovudine: increased risk of haematological toxicity. Notes: Give with or after food. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). WHO Model Formulary for Children 2010 19
    • 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs Paracetamol ATC code: N02Be01 Oral liquid: 25 mg/ml Suppository: 100 mg Tablet: 100 mg to 500 mg Special Notes: Also referred to as acetaminophen. Not recommended for anti-inflammatory use due to lack of proven benefit. Indications: Mild to moderate pain; fever. Precautions: Hepatic impairment; renal impairment; overdosage. Dose: Mild to moderate pain, fever. Oral, rectal: Neonate 10 mg/kg every 6–8 hours as necessary. Maximum 4 doses in 24 hours. If neonate is jaundiced, a 5 mg/kg dose is suitable. Infant or Child 15 mg/kg, up to 1 g, every 4–6 hours as necessary. Maximum 4 doses, or 4 g, in 24 hours. NOTe Infants under 3 months should not be given paracetamol unless advised by a doctor. Hepatic impairment: Dose related toxicity; avoid large doses. Adverse effects: Rare Rash, hypersensitivity, neutropenia, thrombocytopenia, pancytopenia. HePATOTOXICITy Hepatotoxicity (and less frequently renal damage) can occur after paracetamol overdosage. Children in the following situations may be at an increased risk of liver damage from paracetamol overdosage: malnourished, obese, febrile illness, prolonged course, not eaten for a few days or taking liver enzyme inducing drugs. Refer to section 4.2 for more information on paracetamol toxicity. Interactions with other medicines (* indicates severe): Metoclopramide: increased absorption of paracetamol. Warfarin: prolonged regular use of paracetamol possibly enhances anticoagulant effect. Notes: Shake suspension well before use. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 20 WHO Model Formulary for Children 2010
    • 2.1 Non-opioids and non-steroidal anti-inflammatory medicines (NSAIMs) Acetylsalicylic acid ATC code: N02BA01 Suppository: 50 mg to 150 mg Tablet: 100 mg to 500 mg Do not use acetylsalicylic acid in children who have or who are recovering from chickenpox (varicella), influenza, acute febrile illness or flu symptoms due to the rare association with Reye’s syndrome. During treatment with acetylsalicylic acid, changes in behaviour may be an early sign of Reye’s syndrome. Patients and carers should be instructed to contact the health-care provider if these symptoms develop. Special Notes: Also referred to as aspirin. Indications: Management of rheumatic fever, juvenile arthritis and Kawasaki disease. Contraindications: Hypersensitivity (including asthma, angioedema, urticaria or rhinitis) to acetylsalicylic acid or any other NSAIM; for simple analgesia and antipyrexia in children under 16 years (risk of Reye syndrome); active peptic ulceration; haemophilia and other bleeding disorders; hepatic failure. Precautions: Asthma; uncontrolled hypertension; concomitant use of drugs that increase risk of bleeding; previous peptic ulceration; G6PD deficiency; dehydration; renal impairment; hepatic impairment. Dose: Administer with or after food. Juvenile arthritis, rheumatic fever. Oral: Infant or Child up to 130 mg/kg daily in 5–6 divided doses in acute conditions; 80–100 mg/kg daily in divided doses for maintenance. Kawasaki disease. Oral: Neonate initially 8 mg/kg four times daily until afebrile, followed by 5 mg/kg once daily for 6–8 weeks. If no evidence of coronary lesions after 8 weeks, discontinue treatment or seek expert advice. Infant or Child initially 7.5–12.5 mg/kg four times daily until afebrile, followed by 2–5 mg/kg once daily for 6–8 weeks. If no evidence of coronary lesions after 8 weeks, discontinue treatment or seek expert advice. Renal impairment: Increased risk of bleeding and acetylsalicylic acid induced renal impairment. Severe: avoid; increased risk of sodium and water retention; deterioration in renal function; gastrointestinal bleeding. Hepatic impairment: Avoid in severe hepatic impairment; increased risk of gastrointestinal bleeding. Adverse effects: Common Nausea, dyspepsia, gastrointestinal ulceration or bleeding, tinnitus, vertigo, confusion, increased bleeding time. Uncommon Hypersensitivity reactions including angioedema, bronchospasm and rash (including Stevens-Johnson syndrome), iron deficiency anaemia, renal impairment, oesophageal ulceration. Rare Major haemorrhage (including gastrointestinal, subconjunctival or other), blood dyscrasias, oedema, myocarditis, Reye syndrome with subsequent encephalopathy and severe hepatic injury. Interactions with other medicines (* indicates severe): Dexamethasone: increased risk of gastrointestinal bleeding and ulceration; dexamethasone reduces plasma salicylate concentration. WHO Model Formulary for Children 2010 21
    • 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs Enalapril: antagonism of hypotensive effect; increased risk of renal impairment. Fluoxetine: increased risk of bleeding. * Heparin: enhanced anticoagulant effect of heparin. Hydrocortisone: increased risk of gastrointestinal bleeding and ulceration; hydrocortisone reduces plasma salicylate concentration. * Ibuprofen: avoid concomitant use (increased adverse effects); antiplatelet effect of acetylsalicylic acid possibly reduced. * Methotrexate: reduced excretion of methotrexate (increased toxicity). Metoclopramide: enhanced effect of acetylsalicylic acid (increased rate of absorption). Phenytoin: enhancement of effect of phenytoin. Prednisolone: increased risk of gastrointestinal bleeding and ulceration; prednisolone reduces plasma salicylate concentration. Spironolactone: antagonism of diuretic effect. Valproic acid: enhancement of effect of valproic acid. * Warfarin: risk of bleeding due to antiplatelet effect. Notes: Give with or after food. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 2.2 Opioid analgesics Opioid analgesics act on the central nervous system. Morphine is effective in relieving moderate to severe pain, particularly of visceral origin; there is a large variation in patient response. Weaker opioids such as codeine are suitable for mild to moderate pain. Opioid analgesic overdose In overdose, opioids can cause respiratory depression and coma with pinpoint pupils. Naloxone (section 4.2) is a specific antidote. Codeine ATC code: R05DA04 Tablet: 15 mg (phosphate) Special Notes: Drug subject to international control under the Single Convention on Narcotic Drugs (1961). Indications: Mild to moderate pain. Contraindications: Hypersensitivity to codeine or similar drugs; respiratory depression; risk of paralytic ileus. Precautions: Renal impairment; hepatic impairment; reduced respiratory reserve; overdosage (see section 4.2). SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. 22 WHO Model Formulary for Children 2010
    • 2.2 Opioid analgesics Dose: Mild to moderate pain. Oral: Neonate, Infant or Child 0.5–1 mg/kg every 4–6 hours when needed; maximum 240 mg daily. Renal impairment: Moderate to severe: reduce dose or avoid; increased and prolonged effect; increased cerebral sensitivity. Hepatic impairment: Avoid or reduce dose; may precipitate coma. Adverse effects: Common Nausea, vomiting, constipation (mainly with long-term use), drowsiness, dizziness, urinary retention, dry mouth. Uncommon Respiratory depression (dose related), sweating, facial flushing, dependence, euphoria, sedation, headache, pruritus. Rare Syndrome of inappropriate antidiuretic hormone secretion (SIADH), seizures, anaphylaxis. Interactions with other medicines (* indicates severe): Amitriptyline: possibly increased sedation. Chlorpromazine: enhanced sedative and hypotensive effect. Diazepam: enhanced sedative effect. Haloperidol: enhanced sedative and hypotensive effect. Metoclopramide: antagonism of effect of metoclopramide on gastrointestinal activity. * Ritonavir: ritonavir possibly increases plasma concentration of codeine. Notes: Increase fluid and fibre intake to avoid constipation. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Morphine ATC code: N02AA01 Injection: 10 mg (as hydrochloride or sulfate) in 1 ml ampoule Oral liquid: 2 mg (as hydrochloride or sulfate)/ml Tablet: 10 mg (as sulfate) Tablet (prolonged release): 10 mg; 30 mg; 60 mg (as sulfate) Special Notes: extreme caution should be exercised in determining all drug doses in children. There is a risk of misplacing the decimal point with morphine, resulting in a 10 times overdose. NOTe 0.1 milligrams = 100 micrograms. Drug subject to international control under the Single Convention on Narcotic Drugs (1961). Indications: Postoperative pain; severe acute and chronic pain. Contraindications: Respiratory depression; severe respiratory disease; CNS depression; risk of paralytic ileus; raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment); avoid injection in phaeochromocytoma. Precautions: Renal impairment; hepatic impairment; dependence (severe withdrawal symptoms if withdrawn abruptly); hypothyroidism; convulsive disorders; decreased respiratory reserve and acute asthma; hypotension; prostatic hypertrophy; overdosage. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 23
    • 2 Analgesics, antipyretics, NSAIMs, medicines used to treat gout and DMARDs Dose: Pain. SC or IM: Neonate 100 micrograms/kg every 6 hours, adjusted according to response. Infant 1–6 months initially 100–200 micrograms/kg every 6 hours, adjusted according to response. Infant or Child 6 months–2 years initially 100–200 micrograms/kg every 4 hours, adjusted according to response; 2–12 years initially 200 micrograms/kg every 4 hours, adjusted according to response. Usual maximum dose is 15 mg. IV injection over at least 5 minutes: Neonate initially 50 micrograms/kg every 6 hours, adjusted according to response. Infant 1–6 months initially 100 micrograms/kg every 6 hours, adjusted according to response. Infant or Child 6 months–12 years initially 100 micrograms/kg every 4 hours, adjusted according to response. Maximum dose is 15 mg. IV injection and infusion: Neonate initially by intravenous injection (over at least 5 minutes) 25–100 micrograms/kg then by continuous intravenous infusion 5–40 micrograms/kg/hour adjusted according to response. Child 1– 6 months initially by intravenous injection (over at least 5 minutes) 100–200 micrograms/kg then by continuous infusion 10–30 micrograms/kg/hour adjusted to response; 6 months–12 years initially by intravenous injection (over at least 5 minutes) 100–200 micrograms/kg then by continuous intravenous infusion 20–30 micrograms/kg/hour adjusted according to response. Oral: Child 1–12 months initially 80–200 micrograms/kg every 4 hours, adjusted according to response; 1–2 years initially 200–400 micrograms/kg every 4 hours, adjusted according to response; 2–12 years initially 200–500 micrograms/kg (maximum 20 mg) every 4 hours, adjusted according to response. Oral (prolonged release): Child initially 200–800 micrograms/kg every 12 hours, adjusted according to response. Continuous SC infusion: Child 1–3 months 10 micrograms/kg/hour; 3 months–18 years 20 micrograms/kg/hour. Renal impairment: Mild to moderate: reduce dose by 25%. Severe: reduce dose by 50% or avoid; increased and prolonged effect; increased cerebral sensitivity. Hepatic impairment: Avoid or reduce dose, may precipitate coma. Adverse effects: Common Nausea, vomiting, constipation, lightheadedness, dizziness, sedation, sweating, dysphoria, euphoria, dry mouth, anorexia, spasm of urinary and biliary tract, pruritus, rash, sweating, postural hypotension, miosis. Uncommon Respiratory depression (dose related), bradycardia, tachycardia, palpitations. Rare Syndrome of inappropriate antidiuretic hormone secretion (SIADH), anaphylaxis. Interactions with other medicines (* indicates severe): Amitriptyline: possibly increased sedation. Chlorpromazine: enhanced sedative and hypotensive effect. Ciprofloxacin: manufacturer of ciprofloxacin advises avoid premedication with morphine (reduced plasma ciprofloxacin concentration) when ciprofloxacin used for surgical prophylaxis. Diazepam: enhanced sedative effect. 24 WHO Model Formulary for Children 2010
    • 2.4 Disease modifying agents used in rheumatoid disorders (DMARDs) Haloperidol: enhanced sedative and hypotensive effect. Metoclopramide: antagonism of effect of metoclopramide on gastrointestinal activity. * Ritonavir: ritonavir possibly increases plasma concentration of morphine. Notes: Subcutaneous injection not suitable for oedematous patients. Administer intravenous injection slowly over 5 minutes. For continuous intravenous infusion, dilute with glucose 5% or 10% or sodium chloride 0.9%. For neonatal intensive care infusions, dilute 2.5 mg/kg body weight to a final volume of 50 ml with infusion fluid. Prolonged release morphine preparations must not be crushed or chewed. Child must be able to swallow the tablet whole. Doses should be adjusted according to response. References: Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 2.3 Medicines used to treat gout This section has been deleted from the 2nd WHO Model List of Essential Medicines for Children. 2.4 Disease modifying agents used in rheumatoid disorders (DMARDs) There are currently no medicines in this section of the 2nd WHO Model List of Essential Medicines for Children. WHO Model Formulary for Children 2010 25
    • SECTION 3: Antiallergics and medicines used in anaphylaxis 26 WHO Model Formulary for Children 2010
    • 3 Antiallergics and medicines used in anaphylaxis 3 Antiallergics and medicines used in anaphylaxis Allergic disorders are a common problem in children. Allergic conditions include asthma, eczema, urticaria, allergic rhinitis (hayfever) and allergies to foods, medicines and drugs. Allergic reactions which are mild and of limited duration (e.g. urticaria and allergic rhinitis) may not require treatment. However, when symptoms are moderate or persistent, medications such as anti- histamines and corticosteroids may be required. Antihistamines inhibit the wheals, pruritus, sneezing and nasal secretory responses that characterize allergy, and thus relieve allergic symptoms. Corticosteroids suppress or prevent almost all symptoms of inflammation associated with allergy. Steroids should be used for short-term suppression of inflammation, but long-term use of steroids should be avoided, due to the risk of significant side-effects. Allergic emergencies Severe allergic reactions such as anaphylaxis and angioedema are life-threatening emergencies. First-line treatment for these conditions is epinephrine with appropriate resuscitation. Use of other medications in these conditions is secondary. Chlorphenamine ATC code: R06AB04 Injection: 10 mg (hydrogen maleate) in 1 ml ampoule Oral liquid: 2 mg/5 ml Tablet: 4 mg (hydrogen maleate) Special Notes: Also referred to as chlorpheniramine maleate. WHO age/weight restriction: > 1 year. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Allergic conditions including urticaria, angioedema, rhinitis, conjunctivitis and in pruritic skin disorders. Intravenously as an adjunct in the emergency treatment of anaphylactic shock. Contraindications: Hypersensitivity to chlorphenamine or dexchlorpheniramine. Precautions: Asthma; bladder neck obstruction; hepatic insufficiency; narrow angle glaucoma; pyloroduodenal obstruction; sedative effects; stenosing peptic ulcer; symptomatic prostatic hypertrophy. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 27
    • 3 Antiallergics and medicines used in anaphylaxis Dose: Allergy. Oral: Child under 1 year not recommended; 1–2 years 1 mg twice daily; 2–6 years 1 mg every 4–6 hours (maximum 6 mg daily); 6–12 years 2 mg every 4–6 hours (maximum 12 mg daily). Allergic reactions, anaphylaxis (adjunct). SC, IM or IV: Child under 1 year not recommended; 1–6 years 2.5–5 mg; 6–12 years 5–10 mg. Renal impairment: Severe: dose reduction may be required. Hepatic impairment: Sedation caused by chlorphenamine inappropriate in severe liver disease; avoid. Adverse effects: Common Anorexia, nausea, vomiting, epigastric distress, diarrhoea, constipation, drowsiness, somnolence, dry mouth, blurred vision, urinary retention, drying effect throughout the respiratory tract and a thickening of bronchial mucus, headache, weight gain. Uncommon exfoliative dermatitis, cardiac dysrhythmia, hypotension (more severe when used intravenously), paradoxical excitation. Rare Disturbances in smell and taste, facial dyskinesias, blood dyscrasias (including agranulocytosis, thrombocytopenia, pancytopenia and aplastic anaemia), eeG changes, psychotic disorder, liver dysfunction, tremor, seizures, confusion, depression, sleep disturbances. Interactions with other medicines (* indicates severe): Amitriptyline: increased antimuscarinic and sedative effects. Atropine: increased antimuscarinic adverse effects. Diazepam: enhanced sedative effect. Lopinavir: possibly increased plasma concentration of chlorphenamine. Notes: Give intravenous injection over 1 minute. If necessary, injection solution can be diluted with sodium chloride 0.9% injection. Chlorphenamine may cause excitability in children. References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 28 WHO Model Formulary for Children 2010
    • 3 Antiallergics and medicines used in anaphylaxis Dexamethasone ATC code: H02AB02 Injection: 4 mg dexamethasone phosphate (as disodium salt) in 1 ml ampoule Indications: Adjunct in the emergency treatment of anaphylaxis; short-term suppression of inflammation in allergic disorders. Contraindications: Not relevant to emergency use. Precautions: Increased susceptibility to and severity of infection; activation or exacerbation of tuberculosis; amoebiasis; strongyloidiasis; risk of severe chickenpox in non-immune patients (varicella zoster immunoglobulin required if exposed to chickenpox); avoid exposure to measles (normal immunoglobulin possibly required if exposed); diabetes mellitus; peptic ulcer; hypertension; corneal perforation; osteoporosis; myasthenia gravis. Dose: Inflammatory and allergic disorders. IM or slow IV injection or infusion: Infant or Child 100–400 micrograms/kg in 1–2 divided doses (maximum 24 mg daily). Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: Incidence of adverse effects is related to dose and duration of treatment. Short courses of high-dose systemic treatment cause fewer adverse effects than prolonged courses of lower doses. Common Nausea, increased susceptibility to infection, masking of signs of infection, sodium and water retention, oedema, hypertension, hypokalaemia, hyperglycaemia, increased appetite, dyspepsia, delayed wound healing, bruising, acne, psychiatric effects (see below). INTRAVeNOUS Transient itching, burning or tingling in perineal area (after intravenous bolus). Rare Peptic ulceration, posterior subcapsular cataracts, glaucoma, hypersensitivity reactions including anaphylaxis. PSyCHIATRIC eFFeCTS Include euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour. Delirium or psychosis is less common. Interactions with other medicines (* indicates severe): Acetylsalicylic acid: increased risk of gastrointestinal bleeding and ulceration; dexamethasone reduces plasma salicylate concentration. Albendazole: plasma albendazole concentration possibly increased. * Amphotericin B: increased risk of hypokalaemia (avoid concomitant use unless dexamethasone needed to control reactions). * Carbamazepine: accelerated metabolism of dexamethasone (reduced effect). Contraceptives, oral: oral contraceptives containing estrogens increase plasma concentration of dexamethasone. Digoxin: increased risk of hypokalaemia. Enalapril: antagonism of hypotensive effect. Erythromycin: erythromycin possibly inhibits metabolism of dexamethasone. Furosemide: antagonism of diuretic effect; increased risk of hypokalaemia. Hydrochlorothiazide: antagonism of diuretic effect; increased risk of hypokalaemia. Ibuprofen: increased risk of gastrointestinal bleeding and ulceration. Insulins: antagonism of hypoglycaemic effect. * Lopinavir: possibly reduced plasma lopinavir concentration. WHO Model Formulary for Children 2010 29
    • 3 Antiallergics and medicines used in anaphylaxis Metformin: antagonism of hypoglycaemic effect. * Methotrexate: increased risk of haematological toxicity. * Phenobarbital: metabolism of dexamethasone accelerated (reduced effect). * Phenytoin: metabolism of dexamethasone accelerated (reduced effect). Praziquantel: plasma praziquantel concentration reduced. Propranolol: antagonism of hypotensive effect. * Rifampicin: accelerated metabolism of dexamethasone (reduced effect). Ritonavir: plasma concentration possibly increased by ritonavir. Salbutamol: increased risk of hypokalaemia if high doses of salbutamol given with dexamethasone. Saquinavir: possibly reduced plasma saquinavir concentration. Spironolactone: antagonism of diuretic effect. Vaccine, influenza: high doses of dexamethasone impair immune response. * Vaccine, live: high doses of dexamethasone impair immune response; avoid use of live vaccines. * Warfarin: anticoagulant effect possibly enhanced or reduced (high-dose dexamethasone enhances anticoagulant effect). References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Epinephrine (Adrenaline) ATC code: C01CA24 Injection: 1 mg (as hydrochloride or hydrogen tartrate) in 1 ml ampoule (1:1000) Intravenous epinephrine should be used with extreme care by specialists only. Special Notes: 1 mg/ml = 1:1000 or 0.1%. Indications: Severe anaphylactic reaction; severe angioedema. Contraindications: Closed-angle glaucoma; use during halothane or cyclopropane anaesthesia. Precautions: Hyperthyroidism; hypertension; diabetes mellitus; heart disease; arrhythmias; psychoneurosis; cerebrovascular disease; phaeochromocytoma; susceptibility to closed-angle glaucoma. Dose: Anaphylaxis. IM: Infant under 6 months 50 micrograms (0.05 ml of 1 mg/ml solution); Infant or Child 6 months–6 years 150 micrograms (0.15 ml of 1 mg/ml solution); Child 6–12 years 300 micrograms (0.3 ml of 1 mg/ml solution). These doses may be repeated at 5 minute intervals, several times if necessary, depending on blood pressure, pulse and respiratory function. IV (if circulation inadequate): Infant or Child 10 micrograms/kg (0.1 ml/kg of the dilute 1 mg/10 ml solution) given over several minutes. 30 WHO Model Formulary for Children 2010
    • 3 Antiallergics and medicines used in anaphylaxis Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nausea, vomiting, anxiety, headache, fear, palpitations, tachycardia, restlessness, tremor, dizziness, dyspnoea, weakness, sweating, pallor, hyperglycaemia. Uncommon excessive increase in blood pressure, ventricular arrhythmias, pulmonary oedema (on excessive dosage or extreme sensitivity), angina, cold extremities, peripheral ischaemia and necrosis (at injection site). Rare Allergic reaction (sodium metabisulfite in some products). OVeRDOSe OR RAPID INTRAVeNOUS ADMINISTRATION Arrhythmias (ventricular and supraventricular), severe hypertension, cerebral haemorrhage, pulmonary oedema. Interactions with other medicines (* indicates severe): Amitriptyline: increased effect or toxicity of epinephrine. * Cyclopropane: may precipitate ventricular arrhythmias. * Ergot derivatives: may precipitate hypertensive crisis Fluoxetine: increased effect or toxicity of epinephrine. * Halothane: may precipitate ventricular arrhythmias. Propranolol: hypertension, bradycardia, resistance to epinephrine effect. Notes: 1 mg/ml = 1:1000 or 0.1%. Inject intramuscular epinephrine into anterolateral aspect of thigh; do not inject into hands, feet, ears, nose, genitals or buttocks. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Hydrocortisone ATC code: H02AB09 Powder for injection: 100 mg (as sodium succinate) in vial Indications: Adjunct in the emergency treatment of anaphylaxis. Contraindications: Not relevant to emergency use. Precautions: Not relevant to emergency use. Dose: Anaphylaxis. IM or IV: Infant under 6 months initially 25 mg up to four times daily adjusted according to response. Infant or Child 6 months–6 years initially 50 mg up to four times daily adjusted according to response. Child 6–12 years initially 100 mg up to four times daily adjusted according to response. Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. WHO Model Formulary for Children 2010 31
    • 3 Antiallergics and medicines used in anaphylaxis Adverse effects: Incidence of adverse effects is related to dose and duration of treatment. Short courses of high-dose systemic treatment cause fewer adverse effects than prolonged courses of lower doses. Common Nausea, increased susceptibility to infection, masking of signs of infection, sodium and water retention, oedema, hypertension, hypokalaemia, hyperglycaemia, increased appetite, dyspepsia, delayed wound healing, bruising, acne, psychiatric effects (including euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour). INTRAVeNOUS Transient itching, burning or tingling in perineal area (after intravenous bolus). Rare Peptic ulceration, posterior subcapsular cataracts, glaucoma, hypersensitivity reactions including anaphylaxis, psychiatric effects (including delirium or psychosis). Interactions with other medicines (* indicates severe): Acetylsalicylic acid: increased risk of gastrointestinal bleeding and ulceration; hydrocortisone reduces plasma salicylate concentration. * Amphotericin B: increased risk of hypokalaemia (avoid concomitant use unless hydrocortisone needed to control reactions). * Carbamazepine: accelerated metabolism of hydrocortisone (reduced effect). Digoxin: increased risk of hypokalaemia. Enalapril: antagonism of hypotensive effect. Erythromycin: erythromycin possibly inhibits metabolism of hydrocortisone. Furosemide: antagonism of diuretic effect; increased risk of hypokalaemia. Hydrochlorothiazide: antagonism of diuretic effect; increased risk of hypokalaemia. Ibuprofen: increased risk of gastrointestinal bleeding and ulceration. Insulins: antagonism of hypoglycaemic effect. Metformin: antagonism of hypoglycaemic effect. * Methotrexate: increased risk of haematological toxicity. * Phenobarbital: metabolism of hydrocortisone accelerated (reduced effect). * Phenytoin: metabolism of hydrocortisone accelerated (reduced effect). Propranolol: antagonism of hypotensive effect. * Rifampicin: accelerated metabolism of hydrocortisone (reduced effect). Ritonavir: plasma concentration possibly increased by ritonavir. Salbutamol: increased risk of hypokalaemia if high doses of salbutamol given with hydrocortisone. Spironolactone: antagonism of diuretic effect. Vaccine, influenza: high doses of hydrocortisone impairs immune response. * Vaccine, live: high doses of hydrocortisone impairs immune response; avoid use of live vaccines. * Warfarin: anticoagulant effect possibly enhanced or reduced (high-dose hydrocortisone enhances anticoagulant effect). References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 32 WHO Model Formulary for Children 2010
    • 3 Antiallergics and medicines used in anaphylaxis Prednisolone ATC code: H02AB06 Oral liquid: 5 mg/ml Tablet: 5 mg; 25 mg Special Notes: Prednisone should be considered equivalent to prednisolone. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Short-term suppression of inflammation. Contraindications: Untreated systemic infection; administration of live vaccines: usually not relevant to emergency treatment. Precautions: Most precautions do not apply for emergency or short-term use. Increased severity of viral infections; recent myocardial infarction; congestive heart failure; renal impairment; hepatic impairment; diabetes mellitus; osteoporosis; glaucoma; corneal perforation; severe psychosis; epilepsy; psoriasis; peptic ulcer; hypothyroidism; history of steroid myopathy. Dose: Oral: Infant or Child 1–2 mg/kg once daily (usual maximum 60 mg), reducing after a few days if appropriate. Increased frequency may be required in certain clinical indications. Renal impairment: Dose reduction not necessary. Hepatic impairment: Adverse effects more common. Adverse effects: Incidence of adverse effects is related to dose and duration of treatment. Short courses of high-dose systemic treatment cause fewer adverse effects than prolonged courses of lower doses. Common Nausea, increased susceptibility to infection, masking of signs of infection, sodium and water retention, oedema, hypertension, hypokalaemia, hyperglycaemia, increased appetite, dyspepsia, delayed wound healing, bruising, acne, psychiatric effects (including euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour). Rare Peptic ulceration, posterior subcapsular cataracts, glaucoma, hypersensitivity reactions including anaphylaxis, psychiatric effects (including delirium and psychosis). Interactions with other medicines (* indicates severe): Acetylsalicylic acid: increased risk of gastrointestinal bleeding and ulceration; prednisolone reduces plasma salicylate concentration. * Amphotericin B: increased risk of hypokalaemia. * Carbamazepine: accelerated metabolism of prednisolone (reduced effect). Ciclosporin: increased plasma concentration of prednisolone. Contraceptives, oral: oral contraceptives containing estrogens increase plasma concentration of prednisolone. Digoxin: increased risk of hypokalaemia. Enalapril: antagonism of hypotensive effect. Erythromycin: erythromycin possibly inhibits metabolism of prednisolone. Furosemide: antagonism of diuretic effect; increased risk of hypokalaemia. Hydrochlorothiazide: antagonism of diuretic effect; increased risk of hypokalaemia. Ibuprofen: increased risk of gastrointestinal bleeding and ulceration. WHO Model Formulary for Children 2010 33
    • 3 Antiallergics and medicines used in anaphylaxis Insulins: antagonism of hypoglycaemic effect. * Methotrexate: increased risk of haematological toxicity. * Phenobarbital: metabolism of prednisolone accelerated (reduced effect). * Phenytoin: metabolism of prednisolone accelerated (reduced effect). Propranolol: antagonism of hypotensive effect. * Rifampicin: accelerated metabolism of prednisolone (reduced effect). Ritonavir: plasma concentration possibly increased by ritonavir. Salbutamol: increased risk of hypokalaemia if high doses of salbutamol given with prednisolone. Spironolactone: antagonism of diuretic effect. Vaccine, influenza: high doses of prednisolone impair immune response. * Vaccine, live: high doses of prednisolone impair immune response; avoid use of live vaccines. * Warfarin: anticoagulant effect possibly enhanced or reduced (high-dose prednisolone enhances anticoagulant effect). Notes: Take the tablets or oral liquid with food to help reduce stomach upset. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 34 WHO Model Formulary for Children 2010
    • SECTION 4: Antidotes and other substances used in poisonings 4.1 Non-specific................................................................................. 36 4.2 Specific ........................................................................................ 38 WHO Model Formulary for Children 2010 35
    • 4 Antidotes and other substances used in poisonings 4 Antidotes and other substances used in poisonings The following notes on treatment of poisoning are guidelines only. It is strongly recommended that poisons information centres or other local sources of expertise be consulted in cases of suspected poisoning. A diagnosis of poisoning is based on history, including details of the poisoning agent, the amount ingested, the time of ingestion, and the results of investigations when appropriate. Symptoms and signs depend on the agent involved and therefore vary widely. Check for burns in or around the mouth, or stridor (abnormal respiratory sounds suggesting laryngeal damage), due to ingestion of corrosives. Admit all children who have ingested iron, pesticides, paracetamol, aspirin, narcotics, antidepressant drugs, paraquat, lithium or warfarin; or who have taken modified-release or prolonged-release dose forms. Children who have ingested corrosives or petroleum products should not be sent home within 6 hours. Supportive care Few patients require active removal of the poison, and most are treated symptomatically with supportive care and monitoring of vital signs. Decontamination Depending on the substance involved and circumstances of poisoning, decontamination of the skin and eyes (with appropriate protection of staff and carers) should be undertaken. For inhaled poisons, removal from the source of poisoning, administration of oxygen and further airway support may be required. Gastric decontamination Gastric decontamination (removal of poisons from the stomach) is most effective within 1 hour of ingestion; after this time it is usually of little benefit. Administration of activated charcoal to prevent further absorption is the treatment of choice for gastric decontamination. Gastric lavage is rarely required. Induction of emesis for treatment of poisoning is not recommended. 4.1 Non-specific Charcoal, activated ATC code: A07BA01 Powder Indications: Reduction of absorption of poisons; active elimination of poisons. Contraindications: Poisoning by hydrocarbons with high potential for harm if aspirated; poisoning by corrosive substances (may prevent visualization of lesions caused by poison); unprotected airway; gastrointestinal tract not intact; bowel obstruction. Precautions: Drowsy or unconscious child (risk of aspiration (intubate before administration via nasogastric or gastric tube)); not effective for poisoning with alcohols, clofenotane (dicophane, dichlorodiphenyltrichloroethane (DDT)), cyanides, malathion, and metal salts including iron and lithium. 36 WHO Model Formulary for Children 2010
    • 4.1 Non-specific Dose: Reduction of absorption of poisons. Oral: Neonate, Infant or Child 1 g/kg (maximum 50 g) as a single dose as soon as possible after ingestion of poison. Active elimination of poisons. Oral: Neonate, Infant or Child 1 g/kg (maximum 50 g) every 4 hours. Renal impairment: Not absorbed; no dose adjustment necessary. Hepatic impairment: Not absorbed; no dose adjustment necessary. Adverse effects: Common Black stools, colicky abdominal pain, nausea, vomiting, constipation or diarrhoea. Rare Bowel obstruction, aspiration, pneumonitis. Interactions with other medicines (* indicates severe): There are no known interactions involving a significant change in effect or where it is recommended to avoid concomitant use. Notes: Administer as soon as possible after ingestion if significant toxicity is anticipated, preferably within 1 hour for greatest effect. Administration after 1 hour is only of any potential benefit in selected poisonings. Refer to specialist texts for advice. The powder should be mixed with fluid such as soft drinks, fruit juice, fruit syrup or chocolate syrup to mask the taste and form a drinkable solution. Mix well immediately prior to ingestion. Do not mix with milk or ice cream. Child must drink slowly to reduce risk of vomiting. Palatability is improved by chilling. Drinking may be easier if mixture is covered or the child drinks with their eyes closed. Unconscious patients in whom decontamination is indicated require intubation to protect their airway. Activated charcoal can be administered via an orogastric or nasogastric tube after aspiration of stomach contents. This route may also be used in conscious patients who refuse, or cannot take, oral charcoal. Laxatives should not be used concurrently with repeat dose activated charcoal because of the risk of fluid and electrolyte disturbances. References: American Academy of Clinical Toxicology; european Association of Poisons Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. Clinical Toxicology, 1999, 37(6):731–751. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO Model Formulary for Children 2010 37
    • 4 Antidotes and other substances used in poisonings 4.2 Specific Acetylcysteine ATC code: V03AB23 Injection: 200 mg/ml in 10 ml ampoule Oral liquid: 10% and 20% Indications: Paracetamol overdosage. Contraindications: There are no contraindications to acetylcysteine when used for paracetamol toxicity. Precautions: Asthma (observe child carefully while slowly administering loading dose over 1–2 hours; do not delay treatment). Dose: Paracetamol overdosage. IV infusion: Neonate, Infant or Child up to 5 years and body weight under 20 kg initially 150 mg/kg in 3 ml/kg glucose 5% and given over 15 minutes, followed by 50 mg/kg in 7 ml/kg glucose 5% and given over 4 hours, then 100 mg/kg in 14 ml/kg glucose 5% and given over 16 hours. over 5 years or body weight over 20 kg initially 150 mg/kg in 100 ml glucose 5% and given over 15 minutes, followed by 50 mg/kg in 250 ml glucose 5% and given over 4 hours, then 100 mg/kg in 500 ml glucose 5% and given over 16 hours. NOTe Continued infusion beyond 20 hours may be required in late presentations or repeated supratherapeutic ingestions if there is evidence of liver toxicity. In such cases, continue the final infusion rate until hepatic transaminases are falling. Oral: Neonate, Infant or Child initially 140 mg/kg, followed by 70 mg/kg every 4 hours for 17 doses, starting 4 hours after loading dose. Renal impairment: No dosage adjustment recommended. Hepatic impairment: No dosage adjustment recommended. Adverse effects: Common Flushing, urticaria, itch. Uncommon Anaphylactoid reaction. Interactions with other medicines (* indicates severe): There are no known interactions involving a significant change in effect or where it is recommended to avoid concomitant use. Notes: For oral therapy, all doses should be given even if paracetamol plasma level has dropped below toxic range. Repeat oral dose if vomiting occurs within 1 hour of administration. emergency treatments such as antihistamines and H2-blockers should be readily available in case of adverse effects. Manufacturer also recommends other infusion fluids, but glucose 5% is preferable. Hypersensitivity-like reactions may be managed by reducing infusion rate or suspending infusion until reaction has settled; specialist advice may be needed. Rash may be managed with an antihistamine, for example chlorphenamine. Acute asthma may be managed with a short-acting beta2-agonist such as salbutamol. 38 WHO Model Formulary for Children 2010
    • 4.2 Specific References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO 17th expert committee on the selection and use of essential medicines. Unedited draft report of the 17th expert committee on the selection and use of essential medicines. WHO Technical Report Series, 18 May 2009 (http://www.who.int/selection_ medicines/committees/expert/17/WeBuneditedTRS_2009.pdf ). WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Atropine ATC code: A03BA01 Injection: 1 mg (as sulfate) in 1 ml ampoule Indications: Treatment of cholinergic effects associated with organophosphate or carbamate poisoning. Contraindications: There are no contraindications to use of atropine for treatment of organophosphate or carbamate poisoning. Precautions: Down syndrome; children; ulcerative colitis; diarrhoea; heart failure; closed-angle glaucoma; myasthenia gravis; gastrointestinal disorders; hyperthyroidism; cardiac disorders; tachycardia; hypertension; hypoxia; fever and in warm environments (monitor temperature and keep patients cool); constipation; delirium. CHILDReN Children are at increased risk for rapid rise in body temperature due to suppression of sweat gland activity. Large doses may cause paradoxical hyperexcitability. DOWN SyNDROMe Down syndrome children have both increased sensitivity to cardiac effects and mydriasis. Children with Down syndrome also have more secretions and may require atropine more frequently. Dose: Organophosphate or carbamate poisoning. IM or IV: Infant or Child 20 micrograms/kg (maximum dose 2 mg) every 5–10 minutes (depending on the severity of poisoning) until the skin becomes flushed and dry, the pupils dilate and tachycardia develops. Dose may be repeated every 1–4 hours for at least 24 hours to maintain atropine effect. Renal impairment: Use with caution. No dosage adjustment necessary. Hepatic impairment: Use with caution. No dosage adjustment necessary. Adverse effects: Common Dry mouth, blurred vision, photophobia, flushing and dryness of skin, rash, difficulty in micturition, constipation, arrhythmias, tachycardia, palpitations, fever. Uncommon Nausea, vomiting, confusion. Rare Closed-angle glaucoma, seizures. Interactions with other medicines (* indicates severe): NOTe Many drugs have antimuscarinic effects; concomitant use of two or more such drugs can increase adverse effects such as dry mouth, urine retention and constipation. Please consider in the context of poisoning treatment whether interactions are clinically relevant. WHO Model Formulary for Children 2010 39
    • 4 Antidotes and other substances used in poisonings Amitriptyline: increased antimuscarinic adverse effects. Chlorphenamine: increased antimuscarinic adverse effects. Chlorpromazine: increased antimuscarinic adverse effects (but reduced plasma chlorpromazine concentration). Haloperidol: possibly reduced effects of haloperidol. Metoclopramide: antagonism of effects of metoclopramide on gastrointestinal activity. Neostigmine: antagonism of effects of neostigmine. Late unopposed bradycardia may result. Pyridostigmine: antagonism of effects of pyridostigmine. Notes: Administer undiluted via rapid intravenous injection as slow injection may result in paradoxical bradycardia. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Calcium gluconate ATC code: A12AA03 Injection: 100 mg/ml in 10 ml ampoule Indications: Magnesium toxicity; severe hyperkalaemia not due to digoxin toxicity; acute hypocalcaemia (including hypocalcaemia caused by ethylene glycol toxicity, hydrofluoric acid ingestion and oxalate poisoning); calcium channel blocker toxicity; topical treatment of hydrofluoric acid burns. Contraindications: There are no contraindications to the use of calcium gluconate for treatment of toxicity or poisoning. Precautions: Conditions associated with hypercalcaemia and hypercalciuria; digoxin therapy; renal impairment. Dose: Urgent correction of acute hypocalcaemia, hyperkalaemia or hypermagnesaemia; calcium channel blocker toxicity. IV: Neonate, Infant or Child 50 mg/kg as a single dose. Maximum dose 200 mg (20 ml). Repeat dose after 10 minutes if necessary. If effective, consider intravenous infusion. Maintenance correction of acute hypocalcaemia, hyperkalaemia or hypermagnesaemia; maintenance treatment of calcium channel blocker toxicity. Continuous IV infusion: Neonate 200 mg/kg daily over 24 hours, adjusted to response. Infant or Child under 2 years 500 mg/kg daily (usual maximum 4 g) over 24 hours. Child over 2 years 4 g over 24 hours. Hydrofluoric acid burns. Topical: Child all ages apply 2.5% calcium gluconate gel to the affected area for at least 30 minutes, usually longer. NOTe To extemporaneously prepare 2.5% calcium gluconate gel, combine 2.5 ml (250 mg) of injection solution in 100 ml of water soluble lubricant, such as K-y Jelly®. 40 WHO Model Formulary for Children 2010
    • 4.2 Specific Renal impairment: Moderate to severe impairment: may require dosage adjustment depending on calcium level. Risk of hypercalcaemia and renal calculi. Hepatic impairment: No dosage adjustment necessary. Adverse effects: Common Gastrointestinal disturbances, constipation, injection site reactions, fall in blood pressure. Uncommon Bradycardia, arrhythmia, peripheral vasodilation. Rare Renal calculi, severe tissue damage with extravasation. Interactions with other medicines (* indicates severe): Please consider in the context of poisoning treatment whether interactions are clinically relevant. Ciprofloxacin: reduced absorption of ciprofloxacin. Digoxin: large intravenous doses of calcium salts can precipitate arrhythmias. Hydrochlorothiazide: increased risk of hypercalcaemia. Levothyroxine: reduced absorption of levothyroxine. Ofloxacin: reduced absorption of ofloxacin. Notes: For intravenous infusion, dilute to 20 mg/ml with glucose 5% or sodium chloride 0.9%. Maximum administration rate is 20 mg/kg/hour (or 10 mg/kg/hour in neonates). For intravenous injection, administer via slow intravenous injection over 5–10 minutes. Avoid extravasation; should not be given by intramuscular or subcutaneous injection. Continuous eCG monitoring is recommended during intravenous calcium administration. Significant hydrofluoric acid poisoning (> 3% of body surface area) may result in marked systemic hypocalcaemia requiring intravenous therapy. References: Brent J et al. Critical care toxicology. Philadelphia, elsevier Mosby, 2005. Dart R, ed. Medical toxicology. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Deferoxamine ATC code: V03AC01 Powder for injection: 500 mg (as mesilate) in vial Special Notes: Also referred to as desferrioxamine. Indications: Acute iron poisoning; chronic iron overload. Precautions: Renal impairment; eye and ear examinations before and at 3 month intervals during treatment are necessary to assess toxicity; aluminium encephalopathy (may exacerbate neurological dysfunction); for all children monitor body weight and height at 3 month intervals (risk of growth restriction with excessive doses). WHO Model Formulary for Children 2010 41
    • 4 Antidotes and other substances used in poisonings Dose: Acute iron poisoning. Slow IV infusion: Neonate, Infant or Child initially 15 mg/kg/hour, reduced after 4–6 hours so that total dose does not exceed 80 mg/kg in 24 hours. Maximum dose 6 g/day. IM: 50 mg/kg/dose every 6 hours. Maximum dose 6 g/day. The preferred route of administration is IV. NOTe It is uncommon to require more than 24 hours therapy for acute iron overdose. Therapeutic end- points to cease infusion are poorly defined but may be indicated by clinically stable patient and serum iron < 60 micromol/l. Chronic iron overload. SC or IV infusion: Infant or Child initially up to 30 mg/kg over 8–12 hours, on 3–7 days per week. For established iron overload the dose is usually between 20 and 50 mg/kg daily. The dose should reflect the degree of iron overload. Use the lowest effective dose. Diagnosis of iron overload. IM: Child 500 mg. Renal impairment: Metal complexes excreted by kidneys (in severe renal impairment dialysis increases rate of elimination). Hepatic impairment: No dosage adjustment necessary. Adverse effects: Common Injection site reactions including redness, pain, swelling, rashes and itch, hypotension (especially when given too rapidly by intravenous injection), fever, arthralgia, myalgia, rash, anaphylactoid reactions. CHRONIC USe Growth retardation, bone deformities (both with high doses). Uncommon Renal failure, non-cardiogenic pulmonary oedema, disturbances of hearing and vision (including lens opacity and retinopathy). CHRONIC USe Neurosensory deafness. Rare Anaphylaxis, acute respiratory distress syndrome, neurological disturbances. CHRONIC USe Bone marrow depression, ocular toxicity, mucormycosis and other unusual infections. Interactions with other medicines (* indicates severe): There are no known significant interactions where it is recommended to avoid concomitant use. Notes: For intravenous or subcutaneous infusion, reconstitute powder with water for injection to a concentration of 100 mg/ml. Dilute with glucose 5% or sodium chloride 0.9%. For intramuscular or subcutaneous administration, reconstitute powder with water for injection to a concentration of 100 mg/ml. No further dilution required. For all children, monitor body weight and height at 3 month intervals (risk of growth restriction with excessive doses). Iron excretion induced by deferoxamine is enhanced by ascorbic acid and ascorbic acid is sometimes prescribed for this purpose. References: Dart R, ed. Medical toxicology. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 42 WHO Model Formulary for Children 2010
    • 4.2 Specific Dimercaprol ATC code: V03AB09 Injection in oil: 50 mg/ml in 2 ml ampoule Indications: Acute heavy metal poisoning by antimony, arsenic, bismuth, gold, mercury, possibly thallium; adjunct (with sodium calcium edetate) in lead poisoning. Contraindications: Not indicated for iron, selenium or cadmium poisoning; severe hepatic impairment (unless due to arsenic poisoning). Precautions: Hypertension; renal impairment; any abnormal reaction such as hyperpyrexia should be assessed; peanut allergy (peanut oil in injection); G6PD deficiency. Dose: Heavy metal poisoning. IM: Infant or Child 2.5–3 mg/kg every 4 hours for 2 days, 2–4 times on the third day, then 1–2 times daily for 10 days or until recovery. Renal impairment: Discontinue or use with extreme caution if impairment develops during treatment. Haemodialysis may be required to remove the chelate in renal failure. Urinary alkalinization prior to commencing treatment may reduce nephrotoxicity caused by dissociation of dimercaprol-metal complexes in acid urine. Hepatic impairment: Severe: avoid use (unless arsenic poisoning). Adverse effects: Common Hypertension, fever, tachycardia, malaise, nausea, vomiting, abdominal pain, salivation, lacrimation, sweating, burning sensation in the mouth, throat and eyes, injection site pain, headache, muscle spasms, tingling of the extremities, feeling of constriction in throat and chest. Uncommon Abscess at injection site. Interactions with other medicines (* indicates severe): * Ferrous salts: avoid concomitant use. Notes: Administer undiluted via deep intramuscular injection. References: Dart R, ed. Medical toxicology. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Naloxone ATC code: V03AB15 Injection: 400 micrograms/ml (hydrochloride) in 1 ml ampoule Indications: Opioid overdosage. Contraindications: There are no contraindications to use of naloxone for treatment of opioid toxicity. Precautions: Physical dependence on opioids or other situations where acute withdrawal syndrome may be precipitated; cardiovascular disease; postoperative patients (may reverse analgesia and increase blood pressure). WHO Model Formulary for Children 2010 43
    • 4 Antidotes and other substances used in poisonings Dose: Opioid overdosage. IV: Neonate, Infant or Child 10 micrograms/kg; if no response give subsequent dose of 100 micrograms/kg. Review diagnosis if respiratory function does not improve. Further doses may be required if respiratory function deteriorates. NOTe Naloxone hydrochloride may be administered in the same doses by intramuscular or subcutaneous injection, but only if the intravenous route is not feasible (slower onset of action). Continuous IV infusion using an infusion pump: Neonate, Infant or Child 5–20 micrograms/kg/hour, adjusted according to response. Renal impairment: excretion of some opioids and/or their active metabolites (codeine, dextropropoxyphene, dihydrocodeine, morphine, pethidine, oxycodone) is delayed in impairment and they will accumulate; extended treatment with naloxone infusion may be required to reverse opioid effect. Hepatic impairment: No dose adjustment necessary. Adverse effects: Common Nausea, vomiting, sweating. Uncommon Tachycardia, ventricular arrhythmias. Rare Cardiac arrest. Interactions with other medicines (* indicates severe): There are no known interactions where it is advised to avoid concomitant use. Notes: For continuous intravenous infusion, dilute to a concentration of 4 micrograms/ml with glucose 5% or sodium chloride 0.9%. For intravenous bolus, administer over 30 seconds as undiluted preparation. Intravenous dose may be repeated every 2–3 minutes until response. After initial response, intravenous dose may need to be repeated every 20–60 minutes due to short duration of action. Do not give naloxone to neonates of mothers who have been taking methadone or heroin. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Penicillamine ATC code: M01CC01 Solid oral dosage form: 250 mg Penicillamine has been associated with fatalities due to agranulocytosis, aplastic anaemia, thrombocytopenia, Goodpasture syndrome and myasthenia gravis. Discontinue therapy if white blood cell count < 3.5 x 109/L. Temporarily discontinue treatment if the platelet count < 100 x 109/L. Patients and carers should be warned to promptly report any symptoms suggesting toxicity. Special Notes: Also referred to as D-penicillamine. Consider use of other metal chelators with better side-effect profile, including sodium calcium edetate and 2,3-dimercaptosuccinic acid if available. Indications: Heavy metal poisoning, particularly lead and copper. 44 WHO Model Formulary for Children 2010
    • 4.2 Specific Contraindications: Hypersensitivity; lupus erythematosus; pregnancy. Precautions: Monitor blood counts and urine tests throughout treatment; concomitant nephrotoxic drugs; renal impairment; avoid concurrent gold, chloroquine or immunosuppressive treatment; avoid oral iron within 2 hours of a dose; penicillin hypersensitivity (risk of cross-reactivity). PATIeNT ADVICe Warn patient or carer to tell doctor immediately if sore throat, fever, infection, non-specific illness, unexplained bleeding and bruising, purpura, mouth ulcers or rash develop. Dose: Heavy metal poisoning, particularly lead and copper. Oral: Child all ages 7.5 mg/kg 3–4 times daily. Duration of therapy depends on pretreatment blood levels and may vary from 4–12 weeks. Renal impairment: Mild impairment: reduce dose and monitor renal function or avoid. Moderate to severe impairment: avoid. Hepatic impairment: No dosage adjustment necessary. Adverse effects: Common Rash, anorexia, nausea, vomiting, taste disturbance. Uncommon Mouth ulcers, fever, allergy, itching, urticaria, proteinuria. Rare Haematuria, thrombocytopenia, leukopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, nephrotic syndrome, lupus erythematosus, Goodpasture syndrome, myasthenia gravis, polymyositis, breast enlargement, hepatic dysfunction, alopecia, pemphigus, dermatomyositis, Stevens-Johnson syndrome. Interactions with other medicines (* indicates severe): Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of penicillamine. Digoxin: plasma concentration of digoxin possibly reduced. Ferrous salts: oral ferrous salts reduce absorption of penicillamine. Ibuprofen: possible increased risk of nephrotoxicity. Isoniazid: penicillamine potentiates isoniazid. Zinc sulfate: absorption of penicillamine and zinc sulfate reduced. Notes: Give on an empty stomach, at least 1 hour before meals or 2 hours after. Separate from milk, food or other drugs by at least 1 hour. For lead poisoning, continue treatment until urinary lead stabilized at less than 500 micrograms/day. Adverse effects may be minimized by starting with a small dose and gradually increasing while monitoring for adverse effects. Monitoring is strongly recommended. Measure urine and blood concentration of the intoxicating metal weekly. Perform complete blood count and urinalysis twice weekly for the first month, then every 2 weeks for 6 months and monthly thereafter. Monitor liver function every 6 months. Monitor patient’s skin, lymph nodes and body temperature. References: Dart R, ed. Medical toxicology. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). WHO Model Formulary for Children 2010 45
    • 4 Antidotes and other substances used in poisonings Sodium calcium edetate ATC code: V03AB03 Injection: 200 mg/ml in 5 ml ampoule Patients with lead encephalopathy and cerebral oedema may experience a lethal increase in intracranial pressure following intravenous infusion; the intramuscular route is preferred for these patients. In cases where the intravenous route is necessary, avoid rapid infusion. Special Notes: Also referred to as calcium disodium edetate, calcium disodium versenate, ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetic acid, calcium disodium edathamil, calcium eDTA, calcium disodium eDTA and edetate calcium disodium. Usually given in conjunction with dimercaprol for lead poisoning. To avoid potentially serious errors, the abbreviation eDTA should never be used. Consider use of oral succimer (2,3-dimercaptosuccinic acid) if available in asymptomatic or minimally symptomatic patients due to better safety profile. Indications: Heavy metal poisoning, particularly lead; lead encephalopathy. Contraindications: Anuria; active renal disease; hepatitis. Precautions: Renal impairment; establish urine flow before treatment. Dose: Heavy metal poisoning, particularly lead, without encephalopathy. Continuous IV infusion: Child all ages 20–30 mg/kg per day for up to 5 days. OR Deep IM: Child all ages 20–30 mg/kg per day in 2–3 divided doses every 8–12 hours for up to 5 days. NOTe Depending on blood lead level, additional courses may be necessary. A second course can be given with a 48 hour interval between the first and second courses, and a third course can be given with a 48 hour interval after the second course. Specialist texts should be consulted for further information on heavy metal poisoning other than lead. Lead encephalopathy. Continuous IV infusion: Child all ages 30 mg/kg per day for 5 days. OR If evidence of cerebral oedema or increased intracranial pressure, intramuscular administration is recommended. Deep IM: Child all ages 30 mg/kg per day in 2–3 divided doses every 8–12 hours for 5 days. NOTe Depending on blood lead level, additional courses may be necessary. A second course can be given with a 48 hour interval between the first and second courses, and a third course can be given with a 48 hour interval after the second course. Renal impairment: Reduce dose in all degrees of renal impairment. Use with extreme caution. Hepatic impairment: No dosage reduction necessary. Adverse effects: Common Sneezing, nasal congestion, numbness, tingling, nausea, diarrhoea, abdominal cramps, fever, malaise, headache, myalgia, thirst, chills. Uncommon Renal tubular necrosis, pain at injection site, thrombophlebitis (if given too rapidly or as too concentrated a solution), lacrimation, transient hypotension. Rare Mucocutaneous (mucous membrane) lesions. 46 WHO Model Formulary for Children 2010
    • 4.2 Specific Interactions with other medicines (* indicates severe): Zinc insulin: interferes with zinc insulin by chelating zinc. Steroids: enhanced renal toxicity. Notes: For intravenous infusion, dilute to a concentration not more than 30 mg/ml with glucose 5% or sodium chloride 0.9%; give over at least 1 hour. Dimercaprol concomitant therapy recommended in symptomatic lead poisoning. Blood lead levels will determine if subsequent courses are required. References: Dart R, ed. Medical toxicology. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2004. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO Model Formulary for Children 2010 47
    • SECTION 5: Anticonvulsants/antiepileptics 48 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics 5 Anticonvulsants/antiepileptics Guiding principles for drug treatment of epilepsy in children The aim of drug treatment for epilepsy is to prevent the recurrence of seizures. Treatment of epilepsy in children should also include counselling of the patient and family, treatment of underlying causes where possible, avoidance of precipitating factors, and safety education. Guiding principles for drug treatment include the following: • Start with a low dose and increase gradually until seizures are controlled, the maximum dose is reached or there are significant side-effects. • Aim for single drug therapy (approximately 70% of children will achieve seizure control on a single drug). • Monitor plasma drug concentrations in some situations. • Use combination therapy when single drug therapy has failed to control seizures. • Avoid sudden cessation of medication, since this can precipitate uncontrolled seizures. If a drug fails to control seizures, it should be gradually substituted with another, and the first drug should be withdrawn only when the new regimen is mainly established. Interactions Anticonvulsant medication interactions are complex. It is important to check for potential interactions when making any changes to the medication schedule of a child on anticonvulsants. Carbamazepine ATC code: N03AF01 Oral liquid: 20 mg/ml Tablet (chewable): 100 mg; 200 mg Tablet (scored): 100 mg; 200 mg The US Food and Drug Administration (FDA) has issued a warning that all patients who are taking, or starting, any antiepileptic should be monitored for changes in behaviour that could indicate the emergence, or worsening, of suicidal thoughts or behaviour or depression. Rare but potentially fatal blood cell abnormalities (aplastic anaemia and agranulocytosis) have been reported in association with carbamazepine treatment. These mostly occur in the first 3–4 months of treatment. Stevens-Johnson syndrome and toxic epidermal necrolysis may occur. Patients and/or carers should be told how to recognize possible blood disorders and severe skin conditions, and to seek medical attention should they occur. Special Notes: May be referred to as CBZ. Indications: Generalized tonic-clonic and partial seizures. Contraindications: Atrioventricular conduction abnormalities; history of bone marrow depression; porphyria. Precautions: Hepatic impairment; renal impairment; cardiac disease; skin reactions (see Adverse effects); history of blood disorders (monitor blood counts before and during treatment); glaucoma; avoid sudden withdrawal. WHO Model Formulary for Children 2010 49
    • 5 Anticonvulsants/antiepileptics Dose: Generalized tonic-clonic and partial seizures. Oral: Infant or Child initially 5 mg/kg at night or 2.5 mg/kg twice daily, increased by 2.5–5 mg/kg every 3–7 days if necessary; usual maintenance dose 5 mg/kg 2–3 times daily (up to 20 mg/kg daily may be needed). Renal impairment: Use with caution. Severe impairment: administer 75% of dose and monitor serum levels. Hepatic impairment: Metabolism impaired in advanced liver disease. Adverse effects: Common Drowsiness, ataxia, dizziness, blurred vision, diplopia, headache (all dose related), rash, dry mouth, abdominal pain, nausea, vomiting, anorexia, diarrhoea, constipation, asymptomatic hyponatraemia, leukopenia, thrombocytopenia, increased liver enzymes (usually not clinically significant). Rare Severe skin reactions (see below), systemic lupus erythematosus, agranulocytosis, aplastic anaemia, cholestatic jaundice, multi-organ hypersensitivity syndrome (including fever, lymphadenopathy, haematological abnormalities, hepatitis), psychosis, arrhythmia, orofacial dyskinesia, hepatitis, gynaecomastia, galactorrhoea, aggression, jaundice, osteomalacia, confusion, arthralgia. SeVeRe SKIN ReACTIONS Include exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis; may also occur as part of multi-organ hypersensitivity syndrome. Serious reactions mostly occur within the first few months of treatment and are more common in those with the HLA-B*1502 allele, which occurs predominantly in people of Han Chinese or Thai ancestry. Interactions with other medicines (* indicates severe): * Amitriptyline: antagonism of anticonvulsant effect (seizure threshold lowered); accelerated metabolism of amitriptyline (reduced plasma concentration; reduced antidepressant effect). Chloroquine: possibly increased risk of seizures. * Chlorpromazine: antagonism of anticonvulsant effect (seizure threshold lowered). Ciclosporin: accelerated metabolism of ciclosporin (reduced plasma ciclosporin concentration). * Dexamethasone: accelerated metabolism of dexamethasone (reduced effect). Doxycycline: accelerated metabolism of doxycycline (reduced effect). * Erythromycin: increased plasma carbamazepine concentration. Ethosuximide: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of ethosuximide possibly reduced. Fluoxetine: plasma concentration of carbamazepine increased. Furosemide: increased risk of hyponatraemia. * Haloperidol: antagonism of anticonvulsant effect (seizure threshold lowered); metabolism of haloperidol accelerated (reduced plasma concentration). Hydrochlorothiazide: increased risk of hyponatraemia. * Hydrocortisone: accelerated metabolism of hydrocortisone (reduced effect). * Isoniazid: increased plasma carbamazepine concentration (also isoniazid hepatotoxicity possibly increased). Levothyroxine: accelerated metabolism of levothyroxine (may increase levothyroxine requirements in hypothyroidism). * Lopinavir: possibly reduced plasma lopinavir concentration. Mebendazole: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infection). 50 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics * Mefloquine: antagonism of anticonvulsant effect. Miconazole: plasma concentration of carbamazepine possibly increased. Phenobarbital: may be enhanced toxicity without corresponding increase in anticonvulsant effect; reduced plasma concentration of carbamazepine. Incidence of serious side-effects such as Stevens- Johnson syndrome may increase when used in combination. * Phenytoin: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin often lowered but may be raised; plasma concentration of carbamazepine often lowered. Incidence of serious side-effects such as Stevens-Johnson syndrome may increase when used in combination. Praziquantel: plasma praziquantel concentration reduced. * Prednisolone: accelerated metabolism of prednisolone (reduced effect). * Ritonavir: plasma concentration possibly increased by ritonavir. Saquinavir: possibly reduced plasma saquinavir concentration. Spironolactone: increased risk of hyponatraemia. Valproic acid: may be enhanced toxicity without corresponding increase in anticonvulsant effect; reduced plasma concentration of valproic acid; plasma concentration of active metabolite of carbamazepine increased. Vecuronium: antagonism of muscle relaxant effect (recovery from neuromuscular blockade accelerated). * Warfarin: accelerated metabolism of warfarin (reduced anticoagulant effect). Notes: Therapeutic drug monitoring (TDM) is available for carbamazepine but routine monitoring is not required for the majority of patients. Plasma concentration for optimum response 4–12 mg/litre (17–50 micromol/litre). References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Diazepam ATC code: N05BA01 Rectal solution or gel: 5 mg/ml in 0.5 ml; 2 ml and 4 ml tubes. Special Notes: Drug subject to international control under the Convention on Psychotropic Substances (1971). Indications: Status epilepticus; emergency management of recurrent seizures. Contraindications: CNS depression or coma; shock; respiratory depression; acute pulmonary insufficiency; sleep apnoea; severe hepatic impairment; marked neuromuscular respiratory weakness including unstable myasthenia gravis. Precautions: Respiratory disease; muscle weakness and myasthenia gravis; marked personality disorder; hepatic impairment; renal impairment; close observation required until full recovery after sedation; porphyria; neonates and infants. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 51
    • 5 Anticonvulsants/antiepileptics Dose: Status epilepticus, emergency management of recurrent seizures. Rectal: Neonate 1.25–2.5 mg repeated once after 10 minutes if necessary. Infant or Child less than 2 years 5 mg repeated once after 10 minutes if necessary; greater than 2 years 10 mg repeated once after 10 minutes if necessary. NOTe Repeat doses should only be administered under medical supervision. Renal impairment: Severe impairment: consider dose reduction; increased cerebral sensitivity. Hepatic impairment: Reduce dose as may precipitate coma. Severe impairment: avoid use. Adverse effects: Common Drowsiness, sedation, confusion, amnesia, muscle weakness, ataxia, slurred speech. Uncommon Respiratory depression especially with repeat doses, hypotension, paradoxical insomnia, excitability, hallucinations, aggression, injection pain, thrombophlebitis. Rare Blood dyscrasias including neutropenia, agranulocytosis, anaemia, leukopenia and thrombocytopenia. Interactions with other medicines (* indicates severe): Amitriptyline: enhanced sedative effect. Chlorphenamine: enhanced sedative effect. Chlorpromazine: enhanced sedative effect. Codeine: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. Haloperidol: enhanced sedative effect. Halothane: enhanced sedative effect. Isoniazid: metabolism of diazepam inhibited. Ketamine: enhanced sedative effect. Morphine: enhanced sedative effect. Nitrous oxide: enhanced sedative effect. Phenytoin: plasma phenytoin concentrations possibly increased or decreased by diazepam. Rifampicin: metabolism of diazepam accelerated (reduced plasma concentration). * Ritonavir: plasma concentration possibly increased by ritonavir (risk of extreme sedation and respiratory depression; avoid concomitant use). Spironolactone: enhanced hypotensive effect. Thiopental: enhanced sedative effect. References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. 52 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics Lorazepam ATC code: N05BA06 Parenteral formulation: 2 mg/ml in 1 ml ampoule; 4 mg/ml in 1 ml ampoule Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Status epilepticus. Contraindications: CNS depression or coma; shock; respiratory depression; acute pulmonary insufficiency; sleep apnoea; severe hepatic impairment; marked neuromuscular respiratory weakness including unstable myasthenia gravis. Precautions: Respiratory disease; muscle weakness and myasthenia gravis; marked personality disorder; hepatic impairment; renal impairment; close observation required until full recovery after sedation; porphyria; neonates and infants. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Status epilepticus. Slow IV injection: Neonate, Infant or Child 50–100 micrograms/kg (maximum 4 mg) as a single dose, repeated once after 10 minutes if necessary. Renal impairment: Increased sensitivity to CNS effects in renal impairment; use a lower initial dose in severe impairment. Hepatic impairment: Contraindicated in severe hepatic impairment, particularly when hepatic encephalopathy is present. In mild to moderate impairment, use low doses of a short acting benzodiazepine to reduce risk of precipitating coma. Adverse effects: Common Drowsiness, oversedation, light-headedness, memory loss, hypersalivation, ataxia, slurred speech. Uncommon Headache, vertigo, disorientation, confusion, paradoxical excitation, euphoria, aggression, hostility, anxiety, anterograde amnesia, respiratory depression, hypotension. IV INJeCTION Pain and thrombophlebitis, severe hypotension, arrhythmias, respiratory arrest. Rare Blood disorders, including leukopenia and leukocytosis, jaundice, transient elevated liver function tests, allergic reactions, including rash and anaphylaxis. Interactions with other medicines (* indicates severe): Amitriptyline: enhanced sedative effect. Chlorphenamine: enhanced sedative effect. Chlorpromazine: enhanced sedative effect. Codeine: enhanced sedative effect. Enalapril: enhanced hypotensive effect. Furosemide: enhanced hypotensive effect. Haloperidol: enhanced sedative effect. Halothane: enhanced sedative effect. Isoniazid: metabolism of lorazepam inhibited. Ketamine: enhanced sedative effect. Morphine: enhanced sedative effect. WHO Model Formulary for Children 2010 53
    • 5 Anticonvulsants/antiepileptics Nitrous oxide: enhanced sedative effect. Phenytoin: plasma phenytoin concentrations possibly increased or decreased by lorazepam. Rifampicin: metabolism of lorazepam accelerated (reduced plasma concentration). * Ritonavir: plasma concentration possibly increased by ritonavir (risk of extreme sedation and respiratory depression; avoid concomitant use). Spironolactone: enhanced hypotensive effect. Notes: Facilities for managing respiratory depression and hypoventilation such as mask, bag and/or mechanical ventilation should be at hand. ADMINISTRATION For intravenous injection, dilute with an equal volume of sodium chloride 0.9% or water for injection (for neonates, dilute injection solution to a concentration of 100 micrograms/ml). Give slowly into a large vein at a rate not exceeding 50 micrograms/kg over 3–5 minutes. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Phenobarbital ATC code: N03AA02 Injection: 200 mg/ml (phenobarbital sodium) Oral liquid: 3 mg/ml (phenobarbital) Tablet: 15 mg to 100 mg (phenobarbital) Special Notes: Also known as phenobarbitone. Drug subject to international control under the Convention on Psychotropic Substances (1971). Indications: Status epilepticus; generalized tonic-clonic seizures; partial seizures; neonatal seizures. Contraindications: Porphyria; absence seizures. Precautions: Renal impairment; hepatic impairment; respiratory depression; debilitated; depression or suicidal tendencies; may cause behavioural changes in children; avoid sudden withdrawal. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Status epilepticus. Slow IV injection: Neonate, Infant or Child initially 20 mg/kg followed by 2.5–5 mg/kg once or twice daily. Generalized tonic-clonic seizures, partial seizures. Slow IV injection followed by oral: Neonate initial dose 20 mg/kg by slow IV injection followed by 2.5–5 mg/kg orally once daily. Oral: Infant or Child initially 1–1.5 mg/kg twice daily, increased by 2 mg/kg daily as required. Usual maintenance dose 2.5–4 mg/kg once or twice daily. Neonatal seizures. Slow IV injection: Neonate 5–10 mg/kg every 20–30 minutes until control is achieved. Careful clinical monitoring and dosage adjustment are necessary in order to minimize the risk of adverse effects. THeRAPeUTIC DRUG MONITORING Therapeutic drug monitoring should be carried out. Trough plasma concentration for optimum response 15–40 mg/litre (65–170 micromol/litre). 54 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics Renal impairment: Use with caution. Avoid large doses in severe impairment. Hepatic impairment: May precipitate coma. Avoid in severe impairment. Adverse effects: Prolonged use may cause physical dependence. Common Sedation, mental depression, paradoxical insomnia, altered mood and behaviour. Uncommon Ataxia, nystagmus, restlessness, confusion, hypotension. Rare exfoliative dermatitis, toxic epidermal necrolysis and Stevens-Johnson syndrome (erythema multiforme), aggression, hyperactivity in children, megaloblastic anaemia, osteomalacia, Dupuytren contracture, multi-organ hypersensitivity syndrome (including fever, severe skin disease, lymphadenopathy, haematological abnormalities, hepatitis). Interactions with other medicines (* indicates severe): Abacavir: plasma concentration of abacavir possibly reduced. * Amitriptyline: antagonism of anticonvulsant effect (seizure threshold lowered); metabolism of amitriptyline possibly accelerated (reduced plasma concentration). * Carbamazepine: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of carbamazepine reduced. The incidence of serious side effects such as Stevens-Johnson syndrome may increase when used in combination. * Chloramphenicol: metabolism of chloramphenicol accelerated (reduced chloramphenicol concentration). * Chlorpromazine: antagonism of anticonvulsant effect (seizure threshold lowered). * Ciclosporin: metabolism of ciclosporin accelerated (reduced effect). * Dexamethasone: metabolism of dexamethasone accelerated (reduced effect). Doxycycline: metabolism of doxycycline accelerated (reduced plasma concentration). Ethosuximide: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of ethosuximide possibly reduced. Etoposide: possibly reduced plasma concentration of etoposide. Fluoxetine: antagonism of anticonvulsant effect (seizure threshold lowered). Folic acid and folinic acid: plasma concentration of phenobarbital possibly reduced. Griseofulvin: reduction in absorption of griseofulvin (reduced effect). * Haloperidol: antagonism of anticonvulsant effect (seizure threshold lowered); metabolism of haloperidol accelerated (reduced plasma concentration). * Hydrocortisone: metabolism of hydrocortisone accelerated (reduced effect). Levothyroxine: metabolism of levothyroxine accelerated (may increase levothyroxine requirements in hypothyroidism). * Lopinavir: plasma concentration of lopinavir possibly reduced. Mebendazole: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infection). Metronidazole: metabolism of metronidazole accelerated (reduced plasma concentration). Phenytoin: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin often lowered but may be raised; plasma concentration of phenobarbital often raised. The incidence of serious side-effects such as Stevens-Johnson syndrome may be increased when used in combination. * Prednisolone: metabolism of prednisolone accelerated (reduced effect). Quinidine: metabolism of quinidine accelerated (reduced plasma concentration). * Saquinavir: plasma concentration of saquinavir possibly reduced. WHO Model Formulary for Children 2010 55
    • 5 Anticonvulsants/antiepileptics Valproic acid: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of valproic acid reduced; phenobarbital concentration increased. * Warfarin: metabolism of warfarin accelerated (reduced anticoagulant effect). Notes: For therapeutic purposes phenobarbital and phenobarbital sodium may be considered equivalent in effect. ADMINISTRATION For intravenous injection, dilute to a concentration of 20 mg/ml with water for injections; give over 20 minutes (no faster than 1 mg/kg/minute). Tablets may be crushed before administration. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Phenytoin ATC code: N03AB02 Capsule: 25 mg; 50 mg; 100 mg (sodium salt) Injection: 50 mg/ml in 5 ml vial (sodium salt) Oral liquid: 5 mg or 6 mg/ml* (base) Tablet: 25 mg; 50 mg; 100 mg (sodium salt) Tablet (chewable): 50 mg *NOTe The possible availability of such similar strengths can cause confusion in prescribing and dispensing; extreme care must be taken when prescribing or dispensing this dose form. Indications: Status epilepticus; generalized tonic-clonic seizures; partial seizures. Contraindications: Porphyria; sinus bradycardia; heart block. Precautions: Hepatic impairment; avoid sudden withdrawal; renal impairment; monitor blood counts; injection solution alkaline (irritant to tissues); avoid intramuscular administration BLOOD OR SKIN DISORDeRS Patients or their carers should be told how to recognize signs of blood or skin disorders and advised to seek immediate medical attention if symptoms such as sore throat, rash, mouth ulcers, bruising or bleeding develop. Leukopenia which is severe, progressive or associated with clinical symptoms requires withdrawal (if necessary under cover of suitable alternative). SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Status epilepticus. IV: Neonate, Infant or Child 18 mg/kg as a loading dose, then 2.5–5 mg/kg twice daily. Generalized tonic-clonic seizures, partial seizures. Oral: Infant or Child initially 1.5–2.5 mg/kg twice daily, increased gradually according to clinical response and plasma phenytoin concentrations to 2.5–5 mg/kg twice daily. Usual maximum 7.5 mg/kg or 300 mg daily. THeRAPeUTIC DRUG MONITORING Therapeutic drug monitoring is required for optimum response and to avoid unnecessary toxicities. Therapeutic plasma phenytoin concentrations are reduced in the first 3 months of life because of reduced protein binding. Trough plasma concentration for optimum response: Neonate–3 months: 6–15 mg/litre (25–60 micromol/litre); Child 3 months–12 years: 10–20 mg/litre (40–80 micromol/litre). 56 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics Renal impairment: No specific dose adjustment is necessary. However, serum phenytoin protein binding is altered in uraemia which can affect proper interpretation/evaluation of serum phenytoin concentrations. The fraction of unbound phenytoin increases as renal function decreases, partially explained by decreases in serum albumin. In these cases clinical outcomes should be considered before changing doses according to blood levels. Hepatic impairment: Reduce dose to avoid toxicity. Adverse effects: Common Gastric intolerance, sleeplessness, agitation, sedation, confusion, ataxia, nystagmus, diplopia, blurred vision, slurred speech, cerebellar/vestibular symptoms, behavioural disorders, impaired learning (dose related), gingival hypertrophy, acne, coarse facies, hirsutism, impaired cognition, increased seizure frequency, lymph node enlargement, vertigo, rash (discontinue; if mild, reintroduce cautiously but discontinue if recurrence). IV Thrombophlebitis, local skin necrosis. Rare Hallucinations, neurological changes including peripheral neuropathy, choreiform movements, cerebellar atrophy, blood dyscrasias, hyperglycaemia, osteomalacia and rickets, Stevens-Johnson syndrome, toxic epidermal necrolysis, systemic lupus erythematosus, multi-organ hypersensitivity syndrome (including fever, severe skin disease, lymphadenopathy, haematological abnormalities, hepatitis). IV Cardiovascular and central nervous system depression (particularly if administered too rapidly) with arrhythmias, hypotension and cardiovascular collapse, and alterations in respiratory function (including respiratory collapse), ‘purple glove’ syndrome (progressive distal limb oedema, discoloration and pain; may lead to soft tissue necrosis and limb ischaemia). Interactions with other medicines (* indicates severe): Abacavir: plasma concentration of abacavir possibly reduced. Acetylsalicylic acid: enhancement of effect of phenytoin. * Amitriptyline: antagonism of anticonvulsant effect (convulsive threshold lowered); possibly reduced plasma amitriptyline concentration. Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of phenytoin. Azathioprine: possibly reduced absorption of phenytoin. Bleomycin: possibly reduced absorption of phenytoin. * Carbamazepine: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin often lowered but may be raised; plasma concentration of carbamazepine often lowered. Incidence of serious side-effects such as Stevens-Johnson syndrome may be increased in combination therapy. * Chloramphenicol: plasma phenytoin concentration increased (increased risk of toxicity). Chloroquine: possible increased risk of seizures. * Chlorpromazine: antagonism of anticonvulsant effect (convulsive threshold lowered). * Ciclosporin: accelerated metabolism of ciclosporin (reduced plasma ciclosporin concentration). Ciprofloxacin: plasma phenytoin concentration can be increased or decreased by ciprofloxacin. Cyclophosphamide: possibly reduced absorption of phenytoin. Cytarabine: reduced absorption of phenytoin. Dacarbazine: possibly reduced absorption of phenytoin. Dactinomycin: possibly reduced absorption of phenytoin. Daunorubicin: possibly reduced absorption of phenytoin. * Dexamethasone: metabolism of dexamethasone accelerated (reduced effect). Diazepam: plasma phenytoin concentration possibly increased or decreased by diazepam. WHO Model Formulary for Children 2010 57
    • 5 Anticonvulsants/antiepileptics Digoxin: plasma concentration of digoxin possibly reduced. Doxorubicin: possibly reduced absorption of phenytoin. Doxycycline: increased metabolism of doxycycline (reduced plasma concentration). * Ethosuximide: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin possibly increased; plasma concentration of ethosuximide possibly reduced. Etoposide: possibly reduced absorption of phenytoin and possibly reduced plasma concentration of etoposide. * Fluconazole: plasma concentration of phenytoin increased (consider reducing dose of phenytoin). Fluorouracil: metabolism of phenytoin possibly inhibited (increased risk of toxicity). * Fluoxetine: plasma concentration of phenytoin increased. Folic acid and folinic acid: plasma phenytoin concentration possibly reduced. * Haloperidol: antagonism of anticonvulsant effect (convulsive threshold lowered). * Hydrocortisone: metabolism of hydrocortisone accelerated (reduced effect). * Ibuprofen: effect of phenytoin possibly enhanced. * Isoniazid: metabolism of phenytoin inhibited (enhanced effect). Levamisole: plasma phenytoin concentration possibly increased. Levothyroxine: accelerated metabolism of levothyroxine (may increase levothyroxine requirements in hypothyroidism); plasma concentration of phenytoin possibly increased. Lopinavir: plasma lopinavir concentration possibly reduced. Mebendazole: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infections). * Mefloquine: antagonism of anticonvulsant effect. Mercaptopurine: possibly reduced absorption of phenytoin. Methotrexate: reduced absorption of phenytoin; antifolate effect of methotrexate increased. * Metronidazole: metabolism of phenytoin inhibited (increased plasma phenytoin concentration). Phenobarbital: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin often lowered but may be raised; plasma concentration of phenobarbital often raised. Incidence of serious side-effects such as Stevens-Johnson syndrome may be increased in combination therapy. Praziquantel: plasma praziquantel concentration reduced. * Prednisolone: metabolism of prednisolone accelerated (reduced effect). Procarbazine: reduced absorption of phenytoin. * Pyrimethamine: antagonism of anticonvulsant effect; increased antifolate effect. * Quinidine: accelerated metabolism of quinidine (reduced plasma quinidine concentration). * Rifampicin: accelerated metabolism of phenytoin (reduced plasma concentration). Saquinavir: plasma saquinavir concentration possibly reduced. Silver sulfadiazine: possibly increased plasma concentration of phenytoin. Sulfadiazine: plasma phenytoin concentration possibly increased. * Sulfadoxine + pyrimethamine: plasma phenytoin concentration possibly increased; increased antifolate effect. * Sulfamethoxazole + trimethoprim: antifolate effect and plasma phenytoin concentration increased. * Trimethoprim: antifolate effect and plasma phenytoin concentration increased. 58 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics Vaccine, influenza: enhanced effect of phenytoin. Valproic acid: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of valproic acid reduced; plasma concentration of phenytoin increased or possibly reduced. Vecuronium: antagonism of muscle relaxant effect (accelerated recovery from neuromuscular blockade). Vinblastine: possibly reduced absorption of phenytoin. Vincristine: possibly reduced absorption of phenytoin. * Warfarin: accelerated metabolism of warfarin (possibility of reduced anticoagulant effect, but enhancement also reported). Zidovudine: plasma phenytoin concentration increased or decreased by zidovudine. Notes: 100 mg phenytoin sodium contains approximately 92 mg phenytoin. Monitoring of therapeutic concentrations in plasma can improve safety and efficacy. Preferably take with or after food. ADMINISTRATION For administration by mouth: interrupt enteral feeds for at least 1–2 hours before and after giving phenytoin; give with water to enhance absorption. Preferably give phenytoin with or after food. To ensure consistent absorption, administer at the same time in regard to meals. For intravenous administration: before and after administration flush intravenous line with sodium chloride 0.9%. For intravenous injection: give at rate not exceeding 1 mg/kg/minute (maximum 50 mg/minute). For intravenous infusion: dilute to a concentration not exceeding 10 mg/ml with sodium chloride 0.9% and give through an inline filter (0.22–0.5 micron) at a rate not exceeding 1 mg/kg/minute (maximum 50 mg/minute); complete administration within 1 hour of preparation. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Valproic acid (sodium valproate) ATC code: N03AG01 Oral liquid: 40 mg/ml Tablet (crushable): 100 mg Tablet (enteric coated): 200 mg; 500 mg (sodium valproate) Hepatic failure resulting in death may occur. Cases of life-threatening pancreatitis (including fatalities) have been reported in children. HyPeRSeNSITIVITy SyNDROMe Usually occurs in first 6 weeks and can be fatal; symptoms include fever, rash, lymphadenopathy, hepatitis, haematological abnormalities; hepato-renal syndrome may occur. Indications: All forms of epilepsy and seizure disorders including infantile spasms. Contraindications: Active liver disease; family history of severe hepatic dysfunction; pancreatitis; porphyria; previous history of Stevens-Johnson syndrome. WHO Model Formulary for Children 2010 59
    • 5 Anticonvulsants/antiepileptics Precautions: Monitor liver function before and during first 6 months of therapy, especially in patients at most risk (children under 3 years of age, those with metabolic disorders, degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation, or multiple antiepileptic therapy); ensure no undue potential for bleeding before starting and before major surgery or anticoagulant therapy; renal impairment; hepatic impairment; systemic lupus erythematosus; false-positive urine tests for ketones; avoid sudden withdrawal, unless under medical supervision. BLOOD OR HePATIC DISORDeRS Patients or their carers should be told how to recognize signs of blood or liver disorders, and advised to seek immediate medical attention if symptoms including loss of seizure control, malaise, weakness, anorexia, lethargy, oedema, vomiting, abdominal pain, drowsiness, jaundice, or spontaneous bruising or bleeding develop. PANCReATITIS Patients or their carers should be told how to recognize signs of pancreatitis and advised to seek immediate medical attention if symptoms such as abdominal pain, nausea and vomiting develop; discontinue sodium valproate if pancreatitis diagnosed. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery. Dose: All forms of epilepsy and seizure disorders including infantile spasms. Oral: Neonate initially 20 mg/kg once daily. Usual maintenance dose is 10 mg/kg twice daily. Infant or Child initially 5–7.5 mg/kg twice daily. Usual maintenance dose is 12.5–15 mg/kg twice daily. Up to 30 mg/kg twice daily in infantile spasms may be required. If dose exceeds 20 mg/kg twice daily, monitor clinical chemistry and haematological parameters. Renal impairment: Reduce dose and alter dosage according to free serum valproic acid concentration. Renal impairment reduces protein binding; monitoring only total valproic acid serum concentrations may be misleading. Hepatic impairment: Avoid if possible; hepatotoxicity and hepatic failure may occasionally occur (usually in first 6 months). Adverse effects: Common Increased appetite and weight gain, gastrointestinal irritation, nausea, hyperammonaemia, ataxia, tremor, impaired hepatic function, sedation, increased alertness, behavioural disturbances, hearing loss. Uncommon Transient hair loss (regrowth may be curly), inhibition of platelet aggregation, fibrinogen reduction, irregular periods, amenorrhoea, gynaecomastia, toxic epidermal necrolysis, Stevens- Johnson syndrome (erythema multiforme), vasculitis, hirsutism, acne. Rare Oedema, thrombocytopenia, fatal hepatic failure (see Precautions; withdraw treatment immediately if malaise, weakness, lethargy, oedema, abdominal pain, vomiting, anorexia, jaundice, drowsiness or loss of seizure control), pancreatitis (see Precautions; measure plasma amylase if acute abdominal pain), extrapyramidal symptoms, blood disorders (see Precautions; leukopenia, pancytopenia, red cell hypoplasia, Fanconi syndrome), dementia. Interactions with other medicines (* indicates severe): Acetylsalicylic acid: enhancement of effect of valproic acid. * Amitriptyline: antagonism of anticonvulsant effect (seizure threshold lowered). Carbamazepine: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of valproic acid reduced; plasma concentration of active metabolite of carbamazepine increased. * Chloroquine: possible increased risk of seizures. * Chlorpromazine: antagonism of anticonvulsant effect (seizure threshold lowered). 60 WHO Model Formulary for Children 2010
    • 5 Anticonvulsants/antiepileptics Erythromycin: metabolism of valproic acid possibly inhibited (increased plasma concentration). Ethosuximide: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of ethosuximide possibly increased. * Haloperidol: antagonism of anticonvulsant effect (seizure threshold lowered). * Mefloquine: antagonism of anticonvulsant effect. Phenobarbital: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of valproic acid reduced; phenobarbital concentration increased. Phenytoin: may be enhanced toxicity without corresponding increase in anticonvulsant effect; plasma concentration of valproic acid reduced; plasma concentration of phenytoin increased or possibly reduced. Warfarin: anticoagulant effect possibly enhanced. Zidovudine: plasma concentration of zidovudine possibly increased (risk of toxicity). Notes: Plasma concentrations in therapeutic range of 40–100 mg/litre (280–700 micromol/litre); not generally considered useful in assessing control, but higher levels associated with increased incidence of adverse effects; low or undetectable plasma levels are not necessarily an indicator of non-adherence. In patients with confirmed adherence, dose change or co-medication may be needed. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ethosuximide ATC code: N03AD01 Capsule: 250 mg Oral liquid: 50 mg/ml Indications: Absence seizures. Precautions: Hepatic impairment; renal impairment; blood counts and hepatic and renal function tests recommended; avoid sudden withdrawal; porphyria. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. BLOOD DISORDeRS Children or their carers should be told how to recognize signs of blood disorders such as fever, sore throat, mouth ulcers, bruising or bleeding and be advised to seek immediate medical attention if these symptoms occur. Dose: Absence seizures. Oral: Infant or Child 1 month–6 years initially 5 mg/kg (maximum 125 mg) twice daily, increased gradually over 2–3 weeks to a maintenance dose of 10–20 mg/kg (maximum 500 mg) twice daily; 6–12 years initially 250 mg twice daily, increased by 250 mg at intervals of 4–7 days to a usual dose of 500–750 mg twice daily (occasionally, up to a maximum of 1 g twice daily may be needed). WHO Model Formulary for Children 2010 61
    • 5 Anticonvulsants/antiepileptics Renal impairment: Use with caution. Dose reduction not necessary. Hepatic impairment: Use with caution. Dose reduction not necessary. Adverse effects: Common Gastrointestinal disturbances including anorexia, hiccups, nausea and vomiting, epigastric pain (particularly during initial treatment), weight loss, drowsiness, dizziness, ataxia, headache, depression, euphoria. Uncommon Irritability, hyperactivity, sleep disturbances, night terrors, aggressiveness. Rare Rash including Stevens-Johnson syndrome (erythema multiforme), systemic lupus erythematosus, disturbances of liver and renal function, haematological disorders (including leukopenia, agranulocytosis, aplastic anaemia, thrombocytopenia and pancytopenia), gum hyperplasia, swelling of tongue, increased mental state depression with overt suicidal ideation, psychosis, increased libido, myopia, vaginal bleeding. Interactions with other medicines (* indicates severe): * Amitriptyline: antagonism of anticonvulsant effect. Carbamazepine: may enhance toxicity of carbamazepine without corresponding increase in anticonvulsant effect; possibly reduced plasma concentration of ethosuximide. Chloroquine: possible increased risk of seizures. * Chlorpromazine: antagonism of anticonvulsant effect. * Haloperidol: antagonism of anticonvulsant effect (seizure threshold lowered). * Isoniazid: metabolism of ethosuximide inhibited (increased plasma ethosuximide concentration and risk of toxicity). * Mefloquine: antagonism of anticonvulsant effect. Phenobarbital: may enhance toxicity of phenobarbital without corresponding increase in anticonvulsant effect; possibly reduced plasma concentration of ethosuximide. * Phenytoin: may enhance toxicity without corresponding increase in anticonvulsant effect; plasma concentration of phenytoin possibly increased; plasma concentration of ethosuximide possibly reduced. Valproic acid: may enhance toxicity of valproic acid without corresponding increase in anticonvulsant effect; possibly increased plasma concentration of ethosuximide. Notes: Administer with food or milk to reduce gastrointestinal upset. Therapeutic drug monitoring (TDM) is available for ethosuximide but routine monitoring is not required for the majority of patients. Plasma concentration for optimum response 40–100 mg/litre (300–700 micromol/litre). References: Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf. 62 WHO Model Formulary for Children 2010
    • SECTION 6: Anti-infective medicines 6.1 Anthelminthics .......................................................................... 64 6.1.1 Intestinal anthelminthics ............................................................... 64 6.1.2 Antifilarials .................................................................................... 72 6.1.3 Antischistosomals and antitrematode medicines............................. 75 6.2 Antibacterials ............................................................................. 79 6.2.1 Beta-lactam medicines ................................................................... 80 6.2.2 Other antibacterials ....................................................................... 98 6.2.3 Antileprosy medicines .................................................................. 118 6.2.4 Antituberculosis medicines .......................................................... 122 6.3 Antifungal medicines ............................................................... 138 6.4 Antiviral medicines .................................................................. 148 6.4.1 Antiherpes medicines ................................................................... 148 6.4.2 Antiretrovirals .............................................................................. 150 Fixed-dose combinations ............................................................. 151 6.4.2.1 Nucleoside/nucleotide reverse transcriptase inhibitors ............... 163 6.4.2.2 Non-nucleoside reverse transcriptase inhibitors ......................... 180 6.4.2.3 Protease inhibitors..................................................................... 187 6.4.3 Other antivirals............................................................................ 197 6.5 Antiprotozoal medicines .......................................................... 199 6.5.1 Antiamoebic and antigiardiasis medicines .................................... 199 6.5.2 Antileishmaniasis medicines......................................................... 201 6.5.3 Antimalarial medicines ................................................................ 208 6.5.3.1 For curative treatment ............................................................... 208 6.5.3.2 For prophylaxis ......................................................................... 220 6.5.4 Antipneumocystosis and antitoxoplasmosis medicines ................. 225 6.5.5 Antitrypanosomal medicines........................................................ 230 6.5.5.1 African trypanosomiasis ............................................................ 230 6.5.5.2 American trypanosomiasis......................................................... 236 WHO Model Formulary for Children 2010 63
    • 6 Anti-infective medicines 6 Anti-infective medicines 6.1 Anthelminthics 6.1.1 Intestinal anthelminthics Cestode tapeworm infections Cestode infections include intestinal taeniasis and cysticercosis, hymenolepiasis (dwarf tapeworm), diphyllobothriasis and echinococcosis (hydatid disease). Intestinal tapeworm infections are often asymptomatic. There may be loss of appetite, nausea and abdominal pain. Further symptoms may become apparent due to worm migration, depending on the site affected, which can include the pancreas, bile duct and appendix. Intestinal nematode infections Intestinal nematode infections include ascariasis, capillariasis, enterobiasis, hookworm infection, strongyloidiasis, trichostrongyliasis and trichuriasis. Tissue nematode infections Tissue nematode infections include angiostrongyliasis, anisakiasis, cutaneous larva migrans, dracun- culiasis, trichinellosis and visceral larva migrans. Albendazole ATC code: P02CA03 Tablet (chewable): 400 mg Indications: Treatment of hydatid disease (Echinococcus granulosus, E. multilocularis) prior to or not amenable to surgery; hookworms; roundworms; pinworms; threadworms; tapeworm (taeniasis); strongyloidiasis; neurocysticercosis; whipworm; filariasis; hairworm; cutaneous larva migrans; visceral larva migrans and trichinosis. Contraindications: Known hypersensitivity to benzimidazoles; pregnancy. Precautions: Liver function tests and blood counts before treatment and every 2 weeks while on therapy; neurocysticercosis (consider steroid and anticonvulsant therapy); retinal cysticercosis. Dose: Hydatid disease (E. granulosus, E. multilocularis). Oral: Child over 2 years 7.5 mg/kg twice daily with food (maximum 400 mg twice daily) for 28 days, followed by 14 day break, then repeat for 2–3 cycles. Hookworms, roundworms, pinworms, threadworms (ancylostomiasis, necatoriasis, ascariasis, enterobiasis). Oral: Child 12 months–2 years 200 mg as a single dose; greater than 2 years or < 10 kg 400 mg as a single dose before food. Treatment may be repeated in 3 weeks. 64 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Tapeworm (taeniasis), strongyloidiasis. Oral: Child less than 10 kg 200 mg daily before food for 3 days; greater than 10 kg 400 mg daily before food for 3 days. Treatment may be repeated in 3 weeks. Neurocysticercosis. Oral: Child under 60 kg 7.5 mg/kg (maximum dose 400 mg) twice daily after food for 7–30 days. Whipworm (Trichuriasis). Oral: Child greater than 2 years 200–400 mg as a single dose, or in heavier infections, 400 mg daily for 3 days. Treatment may be repeated in 3 weeks. Filariasis for community eradication programmes in combination with diethylcarbamazine or ivermectin. Oral: Child less than 10 kg 200 mg once annually for 5 years; greater than 10 kg 400 mg annually for 5 years. Hairworm (Trichostrongyliasis). Oral: Child greater than 10 kg 400 mg as a single dose. Cutaneous larva migrans. Oral: Child greater than 10 kg 400 mg as a single dose, or 400 mg daily for 3 days. Visceral larva migrans (toxocariasis). Oral: Child all ages 10 mg/kg daily (maximum 400 mg daily) for 5 days. Trichinosis. Oral: Child greater than 10 kg 400 mg daily for 8–14 days. Renal impairment: Renal elimination of albendazole is minimal. Dosage adjustment in patients with impaired renal function does not appear necessary. Hepatic impairment: Patients with liver disease may be more susceptible to bone marrow suppression. Adverse effects: Common or uncommon Headache, nausea, vomiting, diarrhoea, abdominal pain, increased liver function tests, dizziness, fever. Rare Hypersensitivity (itch, rash, urticaria), alopecia, bone marrow depression, hepatitis, cholestatic jaundice, Stevens-Johnson syndrome, pancytopenia, allergic shock if cyst leakage, convulsions and meningism in cerebral disease. Interactions with other medicines (* indicates severe): Dexamethasone: plasma albendazole concentration possibly increased. Praziquantel: increased plasma concentration of active metabolite of albendazole. Notes: To aid administration, tablets may be dispersed in water, or crushed or chewed. Patients being treated for neurocysticercosis should receive appropriate steroid and anticonvulsant therapy as required. Oral or intravenous corticosteroids should be considered to prevent cerebral hypertensive episodes during the first week of treatment. Blood counts should be monitored at the beginning of each 28 day cycle of therapy, and every 2 weeks while on therapy with albendazole in all patients. WHO Model Formulary for Children 2010 65
    • 6 Anti-infective medicines References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Levamisole ATC code: P02Ce01 Tablet: 50 mg; 150 mg (as hydrochloride) Indications: Treatment of ascariasis; hookworm and mixed ascariasis with hookworm infections. Precautions: epilepsy; juvenile idiopathic arthritis; Sjogren syndrome. Dose: Ascariasis (roundworm). Oral: Infant and Child all ages 2.5–3 mg/kg (maximum dose 150 mg) as a single dose. Hookworm and mixed ascariasis with hookworm. Oral: Infant and Child all ages 2.5 mg/kg (maximum dose 150 mg) as a single dose repeated after 7 days if severe infection. Renal impairment: Dose reduction not necessary as only small amounts (approximately 3%) of a dose of levamisole are excreted unchanged in the urine. Hepatic impairment: Use with caution; dose adjustment may be necessary. Adverse effects: Uncommon Abdominal pain, nausea, vomiting, dizziness and headache. Rare Taste disturbances (on prolonged treatment), insomnia, seizures (especially at high doses), influenza-like syndrome, blood disorders, vasculitis, arthralgia, myalgia, rash. Interactions with other medicines (* indicates severe): Alcohol: possibility of disulfiram-like reaction. Phenytoin: plasma phenytoin concentration possibly increased. * Warfarin: anticoagulant effect possibly enhanced. Notes: Leukocyte and platelet counts should be monitored regularly during levamisole therapy. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Mebendazole ATC code: P02CA01 Tablet (chewable): 100 mg; 500 mg Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. 66 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Indications: Treatment of pinworm; threadworm; roundworm; whipworm and hookworm infections. Also for the gastrointestinal phase of trichinosis (Trichinella spiralis) and for capillariasis (Capillaria philippinensis). As a second-line agent in the treatment of hydatid disease (Echinococcus granulosus and E. multilocularis) before surgery or not amenable to surgery and also for toxocariasis. Contraindications: Known hypersensitivity to benzimidazoles; pregnancy. Precautions: Blood counts and liver function tests should be monitored (with high-dose regimens); children < 6 months old. Dose: Threadworms, pinworms. Oral: Child from 6 months up to 10 kg 50 mg as a single dose, if reinfection occurs second dose may be needed after 2 weeks; greater than 10 kg or from 1 year 100 mg as a single dose, if reinfection occurs second dose may be needed after 2 weeks. Whipworms, roundworms, hookworms. Oral: Child from 6 months up to 10 kg 50 mg twice daily for 3 days; greater than 10 kg or from 1 year 100 mg twice daily for 3 days. Capillariasis. Oral: Child all ages from 2 years 200 mg twice daily for 20 days. echinococcus (mebendazole is second-line therapy, albendazole is preferred). Oral: Child all ages from 2 years 15mg/kg/dose three times daily. Toxocariasis: visceral larva migrans (mebendazole is second-line therapy, albendazole is preferred). Oral: Child all ages from 2 years 100–200 mg twice daily for 5 days although doses of up to 1 g/day have been used for 21 days. Severe disease may warrant corticosteroid use. Trichinosis (gastrointestinal phase of illness only). Oral: Child all ages from 2 years 5 mg/kg (maximum 200 mg) twice daily with food for 7 days, severe infection may require concomitant corticosteroid use, late phase anthelminthic therapy not indicated. Renal impairment: Dose reduction not necessary. Hepatic impairment: extensively metabolized in the liver. Hepatic insufficiency: lower dose to prevent toxic levels of mebendazole. Adverse effects: Rare Gastrointestinal disturbances, headache, dizziness, with high doses, allergic reactions, raised liver enzymes, alopecia, bone marrow depression. Interactions with other medicines (* indicates severe): Carbamazepine: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infection). Phenobarbital: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infection). Phenytoin: reduced plasma mebendazole concentration (possibly increase mebendazole dose for tissue infection). Notes: Doses should be taken between meals. WHO Model Formulary for Children 2010 67
    • 6 Anti-infective medicines References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Bartlett JG, ed. Johns Hopkins Point of Care Information Technology (POC-IT) Abx Guide. (PDA reference.) 2003 (with updates 2004–2009). Drugs for parasitic infection. The Medical Letter on Drugs and Therapeutics, 2004, 46:1–12. Gilbert DN et al. The Sanford guide to antimicrobial therapy. 38th ed. Sperryville, Antimicrobial Therapy, 2008. Guerrant RL, Walker DH, Weller PF. Tropical infectious diseases: principles, pathogens, & practice. 2nd ed. Philadelphia, Churchill Livingstone, 2006. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Niclosamide ATC code: P02DA01 Tablet (chewable): 500 mg Special Notes: Niclosamide is listed for use only when praziquantel fails. Indications: A second-line agent for the treatment of tapeworm (Taenia saginata, T. solium, Diphyllobothrium latum, Dipylidium caninum and Hymenolepis nana) infections. Precautions: Chronic constipation (restore regular bowel movement before treatment); give antiemetic before treatment; only active against adult stage of tapeworm (i.e. intestinal stage in host), not effective against larval stage (cysticercosis) (i.e. tissue stage in host). Dose: T. solium infection. Oral: Child under 2 years 500 mg; 2–6 years 1 g; over 6 years 2 g. Doses should be given after a light breakfast, followed after 2 hours by a laxative. T. saginata, Dipylidium caninum and Diphyllobothrium latum infection. Oral: As for T. solium but half the dose may be taken after breakfast and the remainder 1 hour later followed by a laxative after 2 hours. Symptomatic persisting Hymenolepis nana infection. Oral: Child under 2 years 500 mg on the first day then 250 mg daily for 6 days; 2–6 years 1 g on first day then 500 mg daily for 6 days; over 6 years 2 g as a single dose on first day then 1 g daily for 6 days, or 2 g daily for 7 days. Repeated treatment may be necessary to cure intense infections or to eliminate the parasite within a family group or institution. Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nausea, retching, abdominal pain. Uncommon Lightheadedness. Rare Pruritus, autoinfection. Notes: Niclosamide must be chewed thoroughly and then swallowed with a small amount of water. Tablets may be crushed to a fine powder for administration to young children and mixed with a small amount of water to form a paste. The drug has a vanilla taste which is palatable for most children. 68 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Niclosamide is effective but may cause disintegration of T. solium segments and release viable eggs with subsequent cysticercosis (disease secondary to cysticercus encystment of larvae of T. solium in tissues and CNS). Concomitant laxative use 2 hours after niclosamide, although only specifically indicated for T. solium infections, is widely recommended, as the precise species of worm may not be confirmed. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Bartlett JG, ed. Johns Hopkins Point of Care Information Technology (POC-IT) Abx Guide. [PDA reference] 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Niclocide Product Information. Bayer, 1995 (http://www.drugs.com/mmx/niclocide.html, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Praziquantel ATC code: P02BA01 Tablet: 150 mg; 600 mg Indications: Cestodiasis (tapeworm including Taenia solium, Taenia saginata, Diphyllobothrium latum, Hymenolepsis nana). Precautions: SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Ocular or neurocysticercosis; cardiac arrhythmias. NOTe Praziquantel use in neurocysticercosis is controversial, and depends on activity status of disease. Multidisciplinary expert consultation strongly advised (infectious diseases physician, neurosurgeon (if cerebral or spinal), ophthalmologist (if ocular)). Dose: Taenia saginata and T. solium infections. Oral: Child over 4 years 5–10 mg/kg as a single dose. Symptomatic and persisting Hymenolepis nana infection. Oral: Child over 4 years 15–25 mg/kg as a single dose. Repeated treatment may be necessary to cure intense infections or to eliminate the parasite within a family group or institution. Diphyllobothrium latum infection. Oral: Child over 4 years 10–25 mg/kg as a single dose. Cysticercosis, dermal cysticercosis. Oral: Child over 4 years 60 mg/kg daily in three divided doses for 6 days. Active parenchymal neurocysticercosis. Oral: 17–33 mg/kg/dose three times daily for 14 days or for 30 days if giant cysts or subarachnoid cysts are present. Albendazole may be preferred over praziquantel. Renal impairment: Dose reduction not necessary. Hepatic impairment: Consider reducing dose in moderate to severe impairment (increases concentration and half-life). WHO Model Formulary for Children 2010 69
    • 6 Anti-infective medicines Adverse effects: Usually mild and transitory with short courses. Many adverse effects result from death of the parasite and are more severe with a high parasite burden. Symptoms such as papilloedema, retinal haemorrhages, focal seizures and motor weakness may occur in people with neurocysticercosis (due to an intense inflammatory response to dying larvae in CNS). Others such as skin reactions, eosinophilia and fever are also thought to be responses to antigens released from dying parasites. Common Dizziness (dose dependent), headache, malaise, drowsiness, nausea, vomiting, abdominal discomfort (dose dependent), diarrhoea, rectal bleeding, anorexia, colic, reversible rises in hepatic aminotransferases, pruritus, rash. Rare Hypersensitivity reactions including fever, eosinophilia (may be due to dead and dying parasites), arrhythmia. Interactions with other medicines (* indicates severe): Albendazole: increased plasma concentration of active metabolite of albendazole. * Carbamazepine: may significantly decrease praziquantel serum concentration. Chloroquine: plasma praziquantel concentration possibly reduced. * Dexamethasone: plasma praziquantel concentration reduced. * Efavirenz: may significantly decrease praziquantel serum concentration. Erythromycin: may increase praziquantel serum concentrations. * Nevirapine: may significantly decrease praziquantel serum concentration. * Phenobarbital: may significantly decrease praziquantel serum concentration. * Phenytoin: plasma praziquantel concentration reduced. * Rifampicin: increases metabolism of praziquantel and may reduce its concentration to ineffective levels. Ritonavir: may increase praziquantel serum concentrations. Notes: If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced. Swallow whole (unchewed) and take with water during meals. Tablet may be cut into halves or quarters, but do not chew. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Bartlett JG, ed. Johns Hopkins Point of Care Information Technology (POC-IT) Abx Guide. (PDA reference.) 2003 (with updates 2004–2009). Baxter K, ed. Stockley’s drug interactions. 8th ed. London, Pharmaceutical Press, 2008. Biltricide Product Information. Bayer Schering Pharma AG, 2010 (http://www.drugs.com/pro/biltricide.html, accessed 10 February 2010). Drugs for parasitic infection. The Medical Letter on Drugs and Therapeutics, 2004, 46:1–12. Garcia HH et al. A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. New England Journal of Medicine, 2004, 350:249–258. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Maguire JH. Tapeworms and seizures - treatment and prevention. New England Journal of Medicine, 2004, 350:215–217. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. 70 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Pyrantel ATC code: P02CC01 Oral liquid: 50 mg (as embonate)/ml Tablet (chewable): 250 mg (as embonate) Special Notes: Also referred to as pyrantel embonate (eUR), pyrantel pamoate (US). Indications: Treatment of intestinal nematode infections such as roundworm, hairworm, hookworm, pinworm, threadworm and trichinosis. Precautions: Liver disease (reduce dose). Dose: Roundworm (ascariasis), hairworm (trichostrongyliasis). Oral: Child all ages 10 mg/kg as a single dose. Hookworm (Ancylostoma and Necator americanus) infections. Oral: Child all ages 10 mg/kg as a single dose; in severe infections, 10 mg/kg daily for 4 days. Pinworm or threadworm (enterobiasis). Oral: Child all ages 10 mg/kg as a single dose with a second dose after 2–4 weeks. Trichinosis. Oral: Child all ages 10 mg/kg daily for 5 days. Renal impairment: Dose reduction not necessary. Hepatic impairment: Reduce dose in hepatic impairment. Adverse effects: Rare Mild gastrointestinal disturbances, headache, dizziness, drowsiness, insomnia, rash and elevated liver enzymes. Interactions with other medicines (* indicates severe): There are no known interactions where it is recommended to avoid concomitant use. Primaquine: may decrease the effect and levels of pyrantel. Notes: Doses are expressed as base, dose forms expressed as salt. 1 mg of pyrantel base is equivalent to 2.88 mg of pyrantel pamoate or embonate salt. All family members should be treated. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). WHO Model Formulary for Children 2010 71
    • 6 Anti-infective medicines 6.1.2 Antifilarials Loiasis Loiasis is an infection with the filarial nematode Loa loa, and is transmitted by the biting tabanid fly Chrysops. Most infections remain asymptomatic, although the classical migration of the adult worm may be seen across the eye. Lymphatic filariasis Lymphatic filariasis is caused by infection with Wuchereria bancrofti (bancroftian filariasis), Brugia malayi, or B. timori (brugian filariasis). It is characterized by early fevers and lymphangitis, then progressive lymphatic obstruction of the affected area, often a limb. Occult filariasis (tropical pulmonary eosinophilia) is a clinical variant of W. bancrofti infection. Onchocerciasis Onchocerciasis (filariasis or river blindness) is caused by infection with the filarial nematode, Onchocerca volvulus. The vector is the black fly which breeds near fast flowing rivers. Clinically it appears as an itchy papular rash progressing to skin thickening with loss of elasticity and subcutaneous nodules. The eyes are often also involved. Ivermectin ATC code: P02CF01 Tablet (scored): 3 mg; 6 mg Indications: Suppressive treatment of onchocerciasis (also known as river blindness), lymphatic filariasis and strongyloidiasis. Contraindications: Pregnancy (delay treatment until after delivery). Precautions: Loiasis coinfection: may develop life-threatening encephalopathy. Hyper-reactive onchodermatitis: more likely to have serious adverse reactions especially oedema, transient worsening of onchodermatitis. Dose: Onchocerciasis and lymphatic filariasis. Oral: Child over 5 years and over 15 kg 150 micrograms/kg as a single dose once a year or as necessary. Strongyloidiasis. Uncomplicated disease. Oral: Child over 5 years and over 15 kg 200 micrograms/kg once daily for 2 days, take with fatty food. Strongyloidiasis. Immunocompromised patients, complicated or disseminated infection. Oral: Child over 5 years and over 15 kg an extended course of 200 micrograms/kg once daily on days 1, 2, 15 and 16. Cutaneous larva migrans. Oral: Child over 5 years and over 15 kg 200 micrograms/kg daily for 1–2 days. In complicated or disseminated infection, daily dosing may be required and expert advice should be sought. Treatment is not always successful, especially in immunosuppressed patients, and may need to be repeated at monthly intervals or a longer course given. 72 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: In onchocerciasis, adverse effects are more frequent and more severe due to allergic or inflammatory responses to death of the parasite (Mazzotti reaction; see below). Common Urticaria, vertigo, tremor, raised liver enzymes (ALT and AST), decreased leukocyte count, eosinophilia, increased haemoglobin. STRONGyLOIDIASIS Diarrhoea, nausea, dizziness, somnolence, abdominal pain. ONCHOCeRCIASIS Mazzotti reaction (see below). Uncommon Pruritus, rash, mild ocular irritation. STRONGyLOIDIASIS Fatigue, constipation, vomiting, tremor, rash, itch. ONCHOCeRCIASIS Headache. Rare Postural hypotension, leukopenia, anaemia, toxic epidermal necrolysis, Stevens-Johnson syndrome. MAZZOTTI ReACTION Occurs within 3 days of treatment, resulting from death of microfilariae; fever, headache, sore throat, cough, rash, conjunctivitis, arthralgia, myalgia, lymphadenopathy, lymphadenitis, oedema, weakness, tachycardia, nausea and vomiting, diarrhoea. Interactions with other medicines (* indicates severe): Alcohol: may increase bioavailability of ivermectin. Notes: PATIeNT ADVICe Absorption of ivermectin is enhanced when dosage is taken following ingestion of a fatty meal. Orange juice modestly reduces ivermectin absorption. Onchocerciasis This treatment does not kill the adult worm, so you may need further treatment. Strongyloidiasis you will need to have your stools checked to see if the treatment was effective. Drug of choice for strongyloidiasis. After a single dose to treat onchocerciasis, skin microfilariae levels are low for up to 9 months (ivermectin does not kill the adult worm). References: Baxter K, ed. Stockley’s drug interactions. 8th ed. London, Pharmaceutical Press, 2008. eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Diethylcarbamazine ATC code: P02CB02 Tablet: 50 mg; 100 mg (dihydrogen citrate) Indications: Systemic lymphatic filariasis and occult filariasis; loiasis (Loa loa). Contraindications: Pregnancy (delay treatment until after delivery). Precautions: Renal impairment; cardiac disorders; other severe acute disease: delay diethylcarbamazine treatment until after recovery. Alkaline urine (e.g. pH 7.5 to 8); in certain regions (e.g. Ghana), the diet is predominantly vegetarian, which promotes alkaline urine, clinical significance of this is unknown but a dose reduction may be necessary; risk of precipitating meningoencephalitis with heavy Loa loa microfilaraemia. WHO Model Formulary for Children 2010 73
    • 6 Anti-infective medicines Dose: Lymphatic filariasis (bancroftian). Oral: Adult and Child over 10 years 1 mg/kg as a single dose on first day, increased gradually over 3 days to 6 mg/kg daily, preferably in divided doses after meals, for 12 days; under 10 years half the adult dose. Lymphatic filariasis (bancroftian). Mass treatment control programmes. Oral: Adult and Child over 10 years 6 mg/kg in divided doses over 24 hours, once a year; under 10 years half the adult dose. Lymphatic filariasis (brugian). Oral: Adult and Child over 10 years 1 mg/kg as a single dose on first day, increased gradually over 3 days to 3–6 mg/kg daily, preferably in divided doses after meals, for 6–12 days; under 10 years half the adult dose. Lymphatic filariasis (brugian). Mass treatment control programmes. Oral: Adult and Child over 10 years 3–6 mg/kg in divided doses over 24 hours, 6 times at weekly or monthly intervals; under 10 years half the adult dose. Filariasis for community eradication programmes. Oral: Child all ages 6 mg/kg once annually. Loiasis (Loa Loa). Oral: Child all ages 6 mg/kg/day in three divided doses for 12 days. NOTe Corticosteroid and antihistamine cover should be considered for the first 2–3 days of therapy. The above dose regimens are intended only as a guide, since many countries have developed specific treatment regimens. Renal impairment: Moderate to severe: reduce dose; plasma half-life prolonged and urinary excretion considerably reduced. Dose reductions are indicated in patients with renal insufficiency, especially those with an alkaline urine (e.g. pH 8) yet specific dosing guidelines are not available. Hepatic impairment: Dose reduction not necessary. Adverse effects: Usually mild and transitory with short courses. Many adverse effects result from death of the parasite and are more severe and more common with a high parasite burden. Immunological reactions (see below), nodules (palpable subcutaneously and along spermatic cord, formed by recently killed worms), transient lymphangitis and exacerbation of lymphoedema. Uncommon or rare Headache, dizziness, drowsiness, nausea and vomiting. IMMUNOLOGICAL ReACTIONS Usually occur within a few hours of the first dose, subsiding by the fifth day of treatment, including fever, headache, joint pain, dizziness, anorexia, malaise, transient haematuria, urticaria, vomiting, asthma in asthmatics (similar to Mazzotti reaction, induced by disintegrating microfilariae). Interactions with other medicines (* indicates severe): Urinary acidifiers: increased loss of diethylcarbamazine, clinical importance of this is unknown. Urinary alkalinisers (e.g. sodium bicarbonate): decreased loss of diethylcarbamazine, clinical importance of this is unknown. 74 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Notes: Should not be used first line for onchocerciasis. Diethylcarbamazine should be administered after meals. Close medical supervision is necessary particularly in the early phase of treatment. In heavy infections there may be a febrile reaction, and in heavy Loa loa infection there is a small risk of encephalopathy. In such cases treatment must be given under careful in-patient supervision and stopped at the first sign of cerebral involvement (and specialist advice sought). References: Baxter K, ed. Stockley’s drug interactions. 8th ed. London, Pharmaceutical Press, 2008. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 6.1.3 Antischistosomals and antitrematode medicines Fluke infections The intestinal flukes include Fasciolopsis buski, Metagonimus yokogawai, Heterophyes heterophyes, Echinostoma spp. and Gastrodiscoides hominis. The liver flukes include Clonorchis sinensis, Opisthorchis viverrini, O. felineus and Fasciola hepatica. The lung flukes are of the genus Paragonimus. Schistosomiasis Schistosomiasis, a waterborne parasitic infection, is caused by several species of trematode worms (blood flukes). Intestinal schistosomiasis is caused principally by Schistosoma mansoni as well as S. japonicum, S. mekongi and S. intercalatum. Urinary schistosomiasis is caused by S. haematobium. Praziquantel ATC code: P02BA01 Tablet: 600 mg Indications: Intestinal schistosomiasis; urinary schistosomiasis, intestinal, liver and lung fluke infections. Contraindications: Ocular cysticercosis. Precautions: SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Neurocysticercosis (see section 6.1.1 Praziquantel); cardiac arrhythmias. Dose: Trematodiasis. Schistosomiasis. Oral: Child over 4 years 20 mg/kg/dose three times daily for 1 day. Or Schistosoma haematobium and S. mansoni. Oral: Child over 4 years 20 mg/kg/dose twice daily for 1 day. WHO Model Formulary for Children 2010 75
    • 6 Anti-infective medicines S. japonicum and S. mekongi. Oral: Child over 4 years 20 mg/kg/dose three times daily for 1 day. Chlonorchiasis and opisthorchiasis. Oral: Child over 4 years 25 mg/kg/dose three times daily (at 5 hour intervals) for 1 day. Paragonimus westermani. Oral: Child over 4 years 25 mg/kg dose three times daily for 2 days. Renal impairment: Dose reduction not necessary. Hepatic impairment: Consider reducing dose in moderate to severe impairment (increases concentration and half-life). Adverse effects: Usually mild and transitory with short courses. Many adverse effects result from death of the parasite and are more severe with a high parasite burden. Symptoms may include skin reactions, eosinophilia and fever, which are also thought to be responses to antigens released from dying parasites. Common Dizziness (dose-dependent), headache, malaise, drowsiness, nausea, vomiting, abdominal discomfort (dose-dependent), diarrhoea, rectal bleeding, anorexia, colic, reversible rises in hepatic aminotransferases. Rare Hypersensitivity reactions including fever, pruritus, eosinophilia (may be due to dead and dying parasites), arrhythmia. Interactions with other medicines (* indicates severe): Albendazole: increased plasma concentration of active metabolite of albendazole. * Carbamazepine: may significantly decrease praziquantel serum concentration. Chloroquine: plasma praziquantel concentration possibly reduced. * Dexamethasone: plasma praziquantel concentration reduced. * Efavirenz: may significantly decrease praziquantel serum concentration. Erythromycin: may increase praziquantel serum concentration. * Nevirapine: may significantly decrease praziquantel serum concentration. * Phenobarbital: may significantly decrease praziquantel serum concentration. * Phenytoin: plasma praziquantel concentration reduced. * Rifampicin: increases metabolism of praziquantel and may reduce its concentration to ineffective levels. Ritonavir: may increase praziquantel serum concentration. Notes: If the tablets or parts of the tablets are kept in the mouth, a bitter taste (which can promote gagging or vomiting) may be experienced. Swallow tablets whole (unchewed) and take with water during meals. Tablet may be cut into halves or quarters, but do not chew. References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 76 WHO Model Formulary for Children 2010
    • 6.1 Anthelminthics Triclabendazole ATC code: P02BX04 Tablet: 250 mg Indications: Fascioliasis; paragonimiasis. Precautions: Paragonimus infections: treatment in hospital as there may be central nervous system involvement; severe fascioliasis: biliary colic, due to obstruction by dying worms. Dose: Fascioliasis. Oral: Child over 4 years 10 mg/kg as a single dose. Paragonimiasis. Oral: Child over 4 years 10 mg/kg/dose twice daily for 1 day. Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Abdominal pain (predominately right upper quadrant), dizziness, headache, fever, chills. Rare Leukopenia. Notes: Take with food. Ingestion of barley may reduce anthelminthic effectiveness. References: Aronson JK, ed. Meyler’s side effects of drugs. 15th ed. Amsterdam, elsevier, 2006. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Oxamniquine ATC code: P02BA02 Capsule: 250 mg Oral liquid: 50 mg/ml Special Notes: Oxamniquine is listed for use when praziquantel treatment fails. Indications: Intestinal schistosomiasis due to Schistosoma mansoni (acute stage and chronic hepatosplenic disease). Contraindications: Pregnancy: delay treatment until after delivery unless immediate intervention necessary. Precautions: SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. epilepsy or a history of seizures. WHO Model Formulary for Children 2010 77
    • 6 Anti-infective medicines Dose: Intestinal schistosomiasis due to S. mansoni (west Africa, South America, Caribbean islands). Oral: Child under 30 kg 20 mg/kg in 2 divided doses; 30 kg and over 15 mg/kg as a single dose. Intestinal schistosomiasis due to S. mansoni (east and central Africa, Arabian peninsula). Oral: Child all ages 30 mg/kg in 2 divided doses. Intestinal schistosomiasis due to S. mansoni (egypt and southern Africa). Oral: Child all ages 60 mg/kg in divided doses over 2–3 days (maximum single dose 20 mg/kg). Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Dizziness, drowsiness, headache, nausea, vomiting, diarrhoea, intense reddish discoloration of urine, eeG abnormalities, eCG abnormalities, scattered pulmonary infiltrates (Loeffler syndrome). Uncommon Urticaria, pruritic skin rashes, fever, raised liver enzyme values. Rare Changes in creatine kinase, proteinuria, haematuria, myalgia, eosinophilia, epileptiform seizures, hallucinations, excitement. Interactions with other medicines (* indicates severe): There are no known interactions involving a significant change in effect or where it is recommended to avoid concomitant use. Notes: To minimize gastrointestinal side effects, administration after a meal or late in the daytime is recommended. Used in the treatment of schistosomiasis caused by S. mansoni, but not by other Schistosoma spp. References: Aronson JK, ed. Meyler’s side effects of drugs. 15th ed. Amsterdam, elsevier, 2006. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 78 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials 6.2 Antibacterials Choice of a suitable antibacterial drug The choice of an antibacterial drug is based on the identity of the likely pathogen and its antibacterial sensitivity, as well as consideration of various factors relating to the patient (e.g. history of allergy, renal and hepatic function, immune status, severity of illness, ethnic origin and age). Antibacterial policy Local policies often limit the availability of antibacterials in order to achieve reasonable economy consistent with adequate antibacterial cover, and to reduce the development of resistant organisms. A policy may allow a range of drugs for general use, and permit use of other drugs only on the advice of a microbiologist or physician responsible for the control of infectious diseases. Guidelines for the management of specific diseases should be consulted when selecting an antibacterial agent. Before starting therapy The following should be considered before starting antimicrobial therapy: • Viral infections should not be treated with antibacterials. Viral upper respiratory tract infections and uncomplicated diarrhoea do not require antibacterial medications. • When possible, samples should be taken for culture and sensitivity testing. “Blind” antibacterial prescribing for unexplained fever usually leads to further difficulty in establishing the diagnosis. • Knowledge of prevalent organisms and their current sensitivity is of great help in choosing an antibacterial before bacteriological confirmation is available. • The choice of an antibiotic for a particular infection should be as specific as possible, reserving broad-spectrum cover for very unwell patients (e.g. those with severe acute malnutrition) when the infecting organism is either unknown or may be one many different species. Narrowing the spectrum, when possible, minimizes potential resistance and limits toxic effects to the patient. • The dose of an antibacterial varies according to a number of factors including age, weight, hepatic function, renal function and severity of infection. The prescribing of the so-called “standard” dose in serious infections may result in failure of treatment; therefore it is important to prescribe a dose appropriate to the condition. An inadequate dose may also increase the likelihood of antibacterial resistance. On the other hand, for an antibacterial with a narrow margin between its toxic and therapeutic doses (e.g. an aminoglycoside), it is equally important to avoid an excessive dose. In such cases, the concentration of the drug in the plasma may need to be monitored. • The route of administration of an antibacterial often depends on the severity of the infection. Life-threatening infections generally require intravenous therapy. However, antibacterials that are well absorbed can be given by mouth even for some serious infections. When possible, painful intramuscular injections should be avoided in children. • Duration of therapy depends on the nature of the infection and the response to treatment. Courses should not be unduly prolonged because this encourages resistance, and prolonged therapy may also lead to unwanted side-effects and unnecessary expense. However, in certain infections, such as tuberculosis or chronic osteomyelitis, it is necessary to treat for prolonged periods. WHO Model Formulary for Children 2010 79
    • 6 Anti-infective medicines 6.2.1 Beta-lactam medicines Beta-lactam antibiotics include penicillins, cefalosporins and carbapenems. These share a common structure and are bactericidal, through a mechanism of action directed at the bacterial cell wall. Hypersensitivity The most important adverse effect of penicillins is hypersensitivity, which causes a rash, and occasionally anaphylaxis, which can be fatal. Allergic reactions to penicillins occur in 1–10% of exposed individuals, while anaphylactic reactions occur in fewer than 0.05%. Individuals with a history of anaphylaxis, urticaria or rash immediately after penicillin administration are at risk of immediate hypersensitivity with subsequent exposure to penicillins. These individuals should not receive a penicillin, cefalosporin or any other beta-lactam antibiotic. Patients who are allergic to one penicillin will be allergic to them all because hypersensitivity is related to the basic penicillin structure. About 10–15% of penicillin- sensitive patients will be allergic to cefalosporins and other beta-lactams. Individuals with a history of a minor rash (a non-confluent rash restricted to a small area of the body) or a rash occurring more than 72 hours after penicillin administration are possibly not allergic to penicillin. In these individuals, a penicillin should not be withheld unnecessarily for a serious infection. Amoxicillin ATC code: J01CA04 Powder for oral liquid: 125 mg (anhydrous)/5 ml; 250 mg (anhydrous)/5 ml Solid oral dosage form: 250 mg; 500 mg (anhydrous) Indications: Urinary tract infections, upper respiratory tract infections, bronchitis; pneumonia; otitis media; dental abscess and other oral infections; osteomyelitis; Lyme disease; endocarditis prophylaxis; post-splenectomy prophylaxis; gynaecological infections; gonorrhoea; anthrax. Contraindications: Hypersensitivity to penicillins (see section notes); penicillin-associated jaundice or hepatic dysfunction. Precautions: History of allergy (see section notes); renal impairment; erythematous rashes common in glandular fever, cytomegalovirus infection, chronic lymphatic leukaemia and possibly HIV infection; maintain adequate hydration with high doses (risk of crystalluria). Dose: Infections due to sensitive organisms. Oral: Child up to 10 years 125 mg every 8–12 hours, doubled in severe infections; over 10 years 250 mg every 8–12 hours, doubled in severe infections. Otitis media. Oral: 40 mg/kg daily in three divided doses (maximum 3 g daily). Renal impairment: Mild to moderate: risk of crystalluria with high doses. Severe: reduce dose; rashes more common and risk of crystalluria. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, superinfection (including candidiasis), especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. 80 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Rare Anaphylaxis, bronchospasm, tooth discoloration, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity (e.g. seizures with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis. Interactions with other medicines (* indicates severe): Allopurinol: increased risk of rash. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Warfarin: studies have failed to demonstrate an interaction, but common experience in anticoagulant clinics is that INR can be altered by a course of amoxicillin. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Amoxicillin + Clavulanic acid ATC code: J01CR02 Oral liquid: 125 mg amoxicillin + 31.25 mg clavulanic acid/5 ml; 250 mg amoxicillin + 62.5 mg clavulanic acid/5 ml Tablet: 500 mg + 125 mg Indications: Infections due to beta-lactamase producing bacteria (where amoxicillin alone not appropriate) including respiratory tract infections, otitis media, genitourinary and abdominal infections, cellulitis, animal bites, severe dental infections, Haemophilus influenzae, osteomyelitis and surgical prophylaxis. Contraindications: Hypersensitivity to penicillins (see section notes); history of penicillin or amoxicillin with clavulanic acid-associated jaundice or hepatic dysfunction. Precautions: History of allergy (see section notes); renal impairment; erythematous rashes common in glandular fever, cytomegalovirus infection, chronic lymphatic leukaemia and possibly HIV infection; maintain adequate hydration with high doses (risk of crystalluria); hepatic impairment. Dose: Infections due to susceptible beta-lactamase producing organisms. Oral (expressed in terms of amoxicillin): Child under 1 year 20 mg/kg daily in three divided doses; 1–6 years 125 mg every 8 hours; 6–12 years 250 mg every 8 hours; over 12 years 250 mg every 8 hours. This dose can be doubled in severe infections. Renal impairment: Risk of crystalluria with high doses (particularly during parenteral therapy); reduce dose if creatinine clearance less than 30 ml/minute. WHO Model Formulary for Children 2010 81
    • 6 Anti-infective medicines Hepatic impairment: Monitor liver function in liver disease. Cholestatic jaundice reported either during or shortly after treatment; more common in patients over the age of 65 years and in males; duration of treatment should not usually exceed 14 days. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy, transient increases in liver enzymes and bilirubin. Uncommon Dizziness, headache, fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile-associated disease. Rare Anaphylaxis, bronchospasm, tooth discoloration, interstitial nephritis, hepatitis, jaundice, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity (e.g. seizures with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, cholestatic hepatitis (generally less severe than flucloxacillin hepatitis and is usually reversible. Symptoms may appear during, or several weeks after, treatment and may persist for 5–6 weeks. The risk increases with age (> 55 years), male sex and length of treatment). Interactions with other medicines (* indicates severe): Allopurinol: increased risk of rash. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Warfarin: studies have failed to demonstrate an interaction, but common experience in anticoagulant clinics is that INR can be altered by a course of amoxicillin. Notes: The risk of acute liver toxicity has been estimated to be about six times higher with amoxicillin + clavulanic acid than amoxicillin. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ampicillin ATC code: J01CA01 Powder for injection: 500 mg; 1 g (as sodium salt) in vial Not to be given by intrathecal injection as can cause encephalopathy which may be fatal. Indications: Mastoiditis; gynaecological infections; septicaemia; peritonitis; endocarditis; meningitis; cholecystitis; osteomyelitis. Contraindications: Hypersensitivity to penicillins (see section notes). Precautions: History of allergy (see section notes); renal impairment; erythematous rashes common in glandular fever, acute or chronic lymphocytic leukaemia and cytomegalovirus infection. 82 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Dose: Severe infections due to sensitive organisms (e.g. meningitis). IV or IM: Neonate under 7 days 50–100 mg/kg every 12 hours; Neonate 7–21 days 50–100 mg/kg every 8 hours; Neonate 21– 28 days 50–100 mg/kg every 6 hours. Child 1 month–12 years 50 mg/kg every 4–6 hours (maximum 2 g every 4 hours). ADMINISTRATION IV administration is preferred. If IM injection is required, lidocaine can be used to reconstitute the injection to reduce local pain. IV: give over 30 minutes when using doses greater than 50 mg/kg to avoid CNS toxicity, including convulsions. Renal impairment: Severe: reduce dose or frequency. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site, superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. Rare Anaphylaxis, bronchospasm, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity (e.g. convulsions with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis. Interactions with other medicines (* indicates severe): Allopurinol: increased risk of rash. Aminoglycosides: separate in terms of IV administration by 1 hour, preferably, due to inactivation of the aminoglycoside by the penicillin. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Warfarin: studies have failed to demonstrate an interaction, but common experience in anticoagulant clinics is that INR can be altered by a course of amoxicillin. Notes: IV penicillins are physically incompatible with many substances (including aminoglycosides); give separately. Avoid rapid IV administration of large doses as it may result in seizures. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). WHO Model Formulary for Children 2010 83
    • 6 Anti-infective medicines Benzathine benzylpenicillin ATC code: J01Ce08 Powder for injection: 900 mg benzathine benzylpenicillin (= 1.2 million IU) in 5 ml vial; 1.8 g benzathine benzylpenicillin (= 2.4 million IU) in 5 ml vial Do not give by intravenous injection. Indications: Streptococcal pharyngitis; diphtheria; syphilis and other treponemal infections (yaws, pinta, bejel); rheumatic fever prophylaxis. Contraindications: Penicillin hypersensitivity (see section notes); intravascular injection; neurosyphilis. Precautions: History of allergy (see section notes); renal failure. Dose: Do not give by intravenous injection. Streptococcal pharyngitis; primary prophylaxis of rheumatic fever. Deep IM: Child under 30 kg 450–675 mg (600 000–900 000 IU) as a single dose; 30 kg and over 900 mg (1.2 million IU) as a single dose. Secondary prophylaxis of rheumatic fever. Deep IM: Child under 30 kg 450 mg (600 000 IU) once every 3–4 weeks; 30 kg and over 900 mg (1.2 million IU) once every 3–4 weeks. Congenital syphilis (where no evidence of CSF involvement). Deep IM: Child up to 2 years 37.5 mg/kg (50 000 IU/kg) as a single dose. yaws, pinta and bejel. Deep IM: Child 450 mg (600 000 IU) as a single dose. Renal impairment: Severe: neurotoxicity; high doses may cause convulsions. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site, superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. Rare Anaphylaxis, bronchospasm, tooth discoloration, joint pain, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity (e.g. seizures with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis, Jarisch-Herxheimer reaction. This consists of fever, chills, headache, hypotension and flare-up of lesions (due to release of pyrogens from the organisms and endotoxins) during treatment for syphilis and other spirochaete infections. Lasts for 12–24 hours; symptoms can be alleviated by acetylsalicylic acid (aspirin) or prednisolone; can be dangerous in cardiovascular syphilis or where there is serious risk of local damage, e.g. optic atrophy. 84 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials ACCIDeNTAL INTRAVASCULAR ADMINISTRATION May result in severe neurovascular damage. CNS effects, including anxiety, agitation, fear of death and hallucinations (usually resolving in 15–30 minutes, but rarely lasting for up to 24 hours) may also occur. Interactions with other medicines (* indicates severe): Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Notes: Give by deep IM injection only. Give doses > 900 mg (1.2 million IU) as two injections at separate sites. It may require that the dose to be divided into two sites if there is reduced muscle bulk. Absorbed slowly into circulation and hydrolysed to benzylpenicillin; use when prolonged, low concentrations of benzylpenicillin are appropriate and adequate. In adults duration of effect of 900 mg (1.2 million IU) dose is 2–4 weeks. Syringes are not graduated; part syringe dosing is not accurate but is used. Benzathine benzylpenicillin 900 mg = 720 mg benzylpenicillin = 1.2 million IU. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Benzylpenicillin ATC code: J01Ce01 Powder for injection: 600 mg (= 1 million IU); 3 g (= 5 million IU) (sodium or potassium salt) in vial Special Notes: Also known as penicillin G. Indications: Pneumonia; throat infections; otitis media; Lyme disease; streptococcal endocarditis; meningococcal disease; necrotizing enterocolitis; necrotizing fasciitis; leptospirosis; neurosyphilis; anthrax; relapsing fever; actinomycosis; brain abscess; gas gangrene; cellulitis; osteomyelitis. Contraindications: Penicillin hypersensitivity (see section notes); avoid intrathecal route (see section notes). Precautions: History of allergy (see section notes); renal failure; heart failure. Dose: Mild to moderate infections due to sensitive organisms. IV or IM: Neonate under 1 week 50 mg/kg daily in two divided doses; Neonate 1–4 weeks 75 mg/kg daily in three divided doses. Child 1 month–12 years 100 mg/kg daily in four divided doses. Higher doses are used in severe infections (see also below). Meningococcal disease. IV or IM: Premature infant and Neonate under 1 week 100 mg/kg daily in two divided doses. Neonate 1–4 weeks 150 mg/kg daily in three divided doses. Child 1 month–2 years 180–300 mg/kg daily in 4–6 divided doses. WHO Model Formulary for Children 2010 85
    • 6 Anti-infective medicines Suspected meningococcal disease (before transfer to hospital). IV or IM: Infant under 1 year 300 mg. Child 1–9 years 600 mg; 10 years and over 1.2 g. Congenital syphilis. IV: Infant and Child up to 2 years 30 mg/kg twice daily for the first 7 days of life, then 30 mg/kg three times daily for 3 days. IV or IM: Child 2 years and over 120–180 mg/kg (to a maximum of 1.44 g) daily in 4–6 divided doses for 10–14 days. Renal impairment: Severe: maximum 6 g daily; neurotoxicity (high doses may cause convulsions). Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site, superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. Rare Anaphylaxis, bronchospasm, tooth discoloration, joint pains, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to their sodium or potassium content), neurotoxicity (e.g. seizures with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens-Johnson syndrome, toxic epidermal necrolysis, Jarisch-Herxheimer reaction. This consists of fever, chills, headache, hypotension and flare-up of lesions (due to release of pyrogens from the organisms and endotoxins) during treatment for syphilis and other spirochaete infections. Lasts for 12–24 hours; symptoms can be alleviated by acetylsalicylic acid (aspirin) or prednisolone; can be dangerous in cardiovascular syphilis or where there is serious risk of local damage, e.g. optic atrophy. Interactions with other medicines (* indicates severe): Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Notes: Intravenous route preferred for neonates and infants; doses over 1.2 g by intravenous route only. IV penicillins are physically incompatible with many substances (including aminoglycosides); give separately. Avoid rapid IV administration of large doses as it may result in convulsions. Longer administration time is particularly important when using doses of ≥ 50 mg/kg to avoid CNS toxicity. Contains 3.4 mmol (78 mg) sodium per 1.2 g injection. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 86 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Cefalexin ATC code: J01DB01 Powder for reconstitution with water: 25 mg/ml; 50 mg/ml Solid oral dosage form: 250 mg Special Notes: Also referred to as cephalexin. Indications: Infection due to sensitive organisms, urinary tract infections, mild cellulitis. Contraindications: Cefalosporin hypersensitivity. Precautions: Renal impairment; impaired vitamin K synthesis, low vitamin K stores (chronic disease and malnutrition) as increased risk of bleeding; allergy to cefalosporins; a severe or immediate allergic reaction (including urticaria, anaphylaxis or interstitial nephritis) to a penicillin. Dose: Oral: Infant and Child 6.25–12.5 mg/kg/dose every 6 hours. Up to maximum of 25 mg/kg/dose every 6 hours may be used in severe infections. The same daily dose may be given twice daily for uncomplicated urinary tract infections, streptococcal pharyngitis and tonsillitis, skin and soft tissue infections, however this is not recommended if > 500 mg per dose is required. Renal impairment: Reduce dose in moderate impairment. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, electrolyte disturbances. Uncommon Vomiting, headache, dizziness, oral and vaginal candidiasis, Clostridium difficile- associated disease, superinfection, eosinophilia, drug fever. Rare Anaphylactic shock, bronchial obstruction, cholestatic hepatitis, urticaria, haemolytic anaemia, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, arthritis, serum sickness-like syndrome, neurotoxicity (including seizures), blood dyscrasias (e.g. neutropenia (related to dose and treatment duration), thrombocytopenia), bleeding, renal impairment. Interactions with other medicines (* indicates severe): Cefalosporins can cause renal impairment; administration with other drugs which also have this effect may increase risk of nephrotoxicity. Metformin: increase in metformin plasma levels and may increase risk of metformin side-effects (nausea, vomiting, diarrhoea, asthenia, headache). Typhoid vaccine, live: a decreased immunological response to the typhoid vaccine. Notes: Hypersensitivity to cefalosporins occurs in about 0.5–6.5% of penicillin sensitive patients. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). WHO Model Formulary for Children 2010 87
    • 6 Anti-infective medicines Cefazolin ATC code: J01DB04 Powder for injection: 1 g (as sodium salt) in vial Special Notes: WHO age/weight restriction: > 1 month. This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Prophylaxis of infection in surgery; treatment of MSSA in non-anaphylactic penicillin allergy. Contraindications: Cefalosporin hypersensitivity (see section 6.2.1). Precautions: Sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction; see section 6.2.1); moderate renal impairment; false-positive urinary glucose (if tested for reducing substances) and false-positive Coombs’ test; seizure disorders. Dose: Surgical prophylaxis. Deep IM or IV: Infant over 1 month 25 mg/kg (maximum 1 g dose) as a single dose at induction of anaesthesia, repeated if necessary if surgery lasts over 3 hours. Further doses may be given every 6–8 hours postoperatively for 24 hours if necessary, or for up to 5 days in continued risk of infection. Intramuscular administration may be painful and should be avoided where possible. If IM injection is required/necessary cefazolin can be reconstituted with lidocaine 0.5%. Renal impairment: Moderate: reduce dose. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, electrolyte disturbances, pain and inflammation at injection site. Uncommon Vomiting, headache, dizziness, oral and vaginal candidiasis, Clostridium difficile- associated disease, superinfection, eosinophilia, drug fever. Rare Confusion (after large doses in renal failure), anaphylaxis, bronchial obstruction, urticaria, haemolytic anaemia, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, renal impairment including interstitial nephritis, abnormal liver function tests, arthritis, serum sickness-like syndrome, neurotoxicity (including seizures), blood dyscrasias including neutropenia, eosinophilia, thrombocytopenia, leukopenia, thrombocythaemia and bleeding. Interactions with other medicines (* indicates severe): Cefalosporins can cause renal impairment; administration with other drugs which also have this effect may increase risk of nephrotoxicity. Typhoid vaccine, live: a decreased immunological response to the typhoid vaccine. * Warfarin: possibly enhanced anticoagulant effect. Notes: IV products are physically incompatible with many substances; avoid mixing with other drugs. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Pharmacy Department, The Royal Children’s Hospital. Paediatric Injectable Guidelines. 3rd ed. Melbourne, The Royal Children’s Hospital, 2006. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 88 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Ceftriaxone ATC code: J01DD04 Powder for injection: 250 mg; 1 g (as sodium salt) in vial Use with calcium (see Contraindications) and avoid in infants with hyperbilirubinaemia. Special Notes: WHO age/weight restriction: > 41 weeks corrected gestational age. Indications: Serious infections due to sensitive bacteria, including septicaemia, pneumonia and meningitis; osteomyelitis, septic arthritis; Haemophilus influenzae epiglottitis; surgical prophylaxis; prophylaxis of meningococcal meningitis; shigellosis, invasive salmonellosis; endocarditis; gonococcal conjunctivitis; gonorrhoea; pelvic inflammatory disease; Lyme disease. Contraindications: Cefalosporin hypersensitivity (see section 6.2.1); porphyria; neonates with jaundice, hypoalbuminaemia, acidosis or impaired bilirubin binding; concomitant treatment with calcium (ceftriaxone should not be used in neonates less than 28 days of age if they are receiving (or are expected to receive) calcium-containing intravenous products. In patients > 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid). Precautions: Sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction; see also section 6.2.1); severe renal impairment; hepatic impairment if accompanied by renal impairment; premature neonates (may displace bilirubin from serum albumin); treatment longer than 14 days, renal failure, dehydration or concomitant total parenteral nutrition (risk of ceftriaxone precipitation in gallbladder); false-positive urinary glucose (if tested for reducing substances) and false-positive Coombs’ test. Dose: Infections due to susceptible organisms. Deep IM or IV: Neonate 7 days or under 50 mg/kg daily (maximum dose 1 g); Neonate over 7 days 75 mg/kg daily (maximum dose 1 g). Infant and Child under 50 kg 50–100 mg/kg daily (maximum dose 1 g); higher dose reserved for severe infections. Neonatal gonococcal conjunctivitis. IM: Neonate 50 mg/kg as a single dose (maximum 125 mg). Prophylaxis of secondary case of meningococcal meningitis. IM: Child 1 month–12 years 125 mg as a single dose; 12–18 years 250 mg as a single dose. ADMINISTRATION Doses of 50 mg/kg and over should be given by intravenous infusion only. Intramuscular doses over 1 g divided between more than one site. For IM injection: ceftriaxone may be mixed with lidocaine 1% to 450 mg/ml to reduce pain at intramuscular site. Administer by intravenous injection (over at least 3 minutes) or by intravenous infusion (over 30 minutes). Intravenous infusions for neonates should be over 60 minutes (see also Contraindications). Renal impairment: Severe: maximum 50 mg/kg daily (maximum 2 g daily); also monitor plasma concentration if both severe renal impairment and hepatic impairment. Hepatic impairment: Reduce dose and monitor plasma concentration if both hepatic and severe renal impairment. WHO Model Formulary for Children 2010 89
    • 6 Anti-infective medicines Adverse effects: Common Diarrhoea, nausea, rash, electrolyte disturbances, abnormalities in liver function enzymes, pain and inflammation at injection site, thrombocytosis, leukopenia. Uncommon Vomiting, headache, dizziness, oral and vaginal candidiasis, Clostridium difficile- associated disease, superinfection, eosinophilia, drug fever. Rare Anaphylaxis, bronchial obstruction, urticaria, haemolytic anaemia, angioedema, Stevens- Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, arthritis, serum sickness-like syndrome, neurotoxicity (including seizures), blood dyscrasias (including thrombocytopenia, neutropenia, haemolytic anaemia, anaemia, haemolysis), prolongation of prothrombin time, renal impairment, pancreatitis, increased bilirubin, jaundice, pseudolithiasis (dose-dependent, asymptomatic and reversible biliary sludge formation due to calcium-ceftriaxone complex; has been mistaken for gallstones on ultrasound scans and usually resolves after stopping treatment), nephrolithiasis (formation of calcium-ceftriaxone renal stones, sometimes requiring treatment; usually reversible). Interactions with other medicines (* indicates severe): Calcium salts. Ciclosporin: increased risk of ciclosporin toxicity (renal dysfunction, cholestasis, paraesthesia). Lactated Ringer’s solution: formation of ceftriaxone-calcium precipitates and is contraindicated. Ringer’s solution: formation of ceftriaxone-calcium precipitates and is contraindicated. Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). * Warfarin: possibly enhanced anticoagulant effect. Notes: Cefotaxime is preferred to ceftriaxone for Gram-negative septicaemia in neonates as ceftriaxone displaces bilirubin from albumin and may increase risk of bilirubin encephalopathy. However, single dose ceftriaxone is used to treat neonatal gonococcal conjunctivitis. Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (< 28 days of age). Ceftriaxone should not be used in neonates (< 28 days of age) if they are receiving (or are expected to receive) calcium-containing intravenous products. In patients > 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid. Ceftriaxone must not be administered simultaneously with intravenous calcium- containing solutions via a y-site in any age group. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Pharmacy Department, The Royal Children’s Hospital. Paediatric Injectable Guidelines. 3rd ed. Melbourne, The Royal Children’s Hospital, 2006. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 90 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Cloxacillin ATC code: J01CF02 Capsule: 500 mg; 1 g (sodium salt) Powder for injection: 500 mg (as sodium salt) in vial Powder for oral liquid: 125 mg (as sodium salt)/5 ml Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Infections due to beta-lactamase-producing staphylococci including impetigo, cellulitis and other soft-tissue infections; pyomyositis; staphylococcal endocarditis, septicaemia, pneumonia, septic arthritis and osteomyelitis; otitis externa. Contraindications: Hypersensitivity to penicillins (see sections notes). Precautions: History of allergy (see section notes); renal and hepatic impairment; heart failure. Dose: Infections due to susceptible beta-lactamase-producing staphylococci. Oral: Child all ages 12.5–50 mg/kg/dose four times daily, depending upon severity of infection. Oral cloxacillin is not optimal for the treatment of severe infections. Parenteral therapy would be preferred. IM or IV: Child all ages 12.5–50 mg/kg/dose four times daily, depending upon severity of infection. Renal impairment: Severe: reduce dose. Hepatic impairment: Dose reduction not necessary; observe for worsening hepatic function. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site, phlebitis or thrombophlebitis at injection sites, transient increases in liver enzymes and bilirubin, superinfection (including candidiasis). Uncommon Fever, vomiting, Clostridium difficile-associated disease. Rare Contact dermatitis, nail damage, electrolyte disturbances (due to their sodium or potassium content), agranulocytosis, coagulation disorders, jaundice, cholestatic hepatitis, hepatotoxicity, nephrotoxicity, interstitial nephritis, serum sickness-like syndrome, immune hypersensitivity reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis. Interactions with other medicines (* indicates severe): Aminoglycosides: concomitant penicillin and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by 1 hour. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Suggestion: allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid vaccine. Warfarin: increased risk of bleeding. Notes: Take on an empty stomach 30 minutes before meals as the presence of food in the stomach decreases absorption. Cholestatic jaundice may occur up to several weeks after treatment has been stopped; administration for more than 2 weeks and increasing age are risk factors. WHO Model Formulary for Children 2010 91
    • 6 Anti-infective medicines References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Phenoxymethylpenicillin ATC code: J01Ce02 Powder for oral liquid: 250 mg (as potassium salt)/5 ml Tablet: 250 mg (as potassium salt) Special Notes: Also referred to as penicillin V. Indications: Streptococcal pharyngitis; otitis media; cellulitis; mouth infections; secondary prophylaxis of rheumatic fever; post-splenectomy prophylaxis. Contraindications: Hypersensitivity to penicillins (see section notes); serious infections (see section notes). Precautions: History of allergy (see section notes); infectious mononucleosis (high incidence of rash). Dose: Infections due to sensitive organisms. Oral: Child all ages 10–12.5 mg/kg/dose (maximum 500 mg) every 6 hours. Dose may be doubled in severe infections. Secondary prophylaxis of rheumatic fever. Oral: Child all ages 10–12.5 mg/kg/dose (maximum 500 mg) twice daily. Renal impairment: Dosage adjustment not necessary. Hepatic impairment: Dosage adjustment may be necessary in patients with impaired liver function when they also have renal failure. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. Rare Anaphylaxis, bronchospasm, tooth discoloration, joint pains, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, neurotoxicity (e.g. seizures with high doses or impaired renal function), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment), thrombocytopenia), nephropathy (with parenteral use), Stevens- Johnson syndrome, toxic epidermal necrolysis. Interactions with other medicines (* indicates severe): Aminoglycosides: concomitant penicillin and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by 1 hour. Chloramphenicol: decreased antibacterial effectiveness. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Notes: Relatively acid-stable, so it can be given orally. PATIeNT ADVICe Phenoxymethylpenicillin should be taken at least 30 minutes before or 2 hours after food. 92 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Procaine benzylpenicillin ATC code: J01Ce09 Powder for injection: 1 g (= 1 million IU); 3 g (= 3 million IU) in vial Accidental intravascular administration may result in severe neurovascular damage. CNS effects including anxiety, agitation, fear of death and hallucinations (usually resolving in 15–30 minutes, but rarely lasting for up to 24 hours) may also occur. Special Notes: Also referred to as penicillin G procaine. Indications: Syphilis; anthrax; pneumonia; diphtheria; cellulitis; mouth infections; bites. Contraindications: Hypersensitivity to penicillins (see section notes); intravascular injection. Precautions: History of allergy (see section notes); renal failure; sodium restriction, heart failure (some parenteral penicillins have high sodium content); infectious mononucleosis (high incidence of rash). Dose: Never administer intravenously. Pneumonia. Deep IM: Child all ages 50 mg/kg (maximum 1.2 g) daily for 10 days. Congenital syphilis. Deep IM: Child up to 2 years 50 mg/kg daily for 10 days. Renal impairment: Severe: neurotoxicity; high doses may cause convulsions. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site (less common with benzylpenicillin), superinfection (including candidiasis) especially during prolonged treatment with broad-spectrum penicillins, allergy. Uncommon Fever, vomiting, erythema, exfoliative dermatitis, angioedema, Clostridium difficile- associated disease. Rare Anaphylaxis, bronchospasm, interstitial nephritis, serum sickness-like syndrome, haemolytic anaemia, electrolyte disturbances (due to sodium or potassium content), neurotoxicity, Hoigné syndrome (bizzare behaviour, neurological reactions), coagulation disorders, blood dyscrasias (e.g. neutropenia (related to dose and duration of treatment)), nephropathy (with parenteral use), muscular contractures in neonates and infants, Stevens-Johnson syndrome, toxic epidermal necrolysis, Jarisch-Herxheimer reaction (fever, chills, headache, hypotension and flare-up of lesions (due to release of pyrogens from the organisms and endotoxins) during treatment for syphilis and other spirochaete infections. Lasts for 12–24 hours; symptoms can be alleviated by acetylsalicylic acid (aspirin) or prednisolone; can be dangerous in cardiovascular syphilis or where there is serious risk of local damage, e.g. optic atrophy). WHO Model Formulary for Children 2010 93
    • 6 Anti-infective medicines Interactions with other medicines (* indicates severe): Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Methotrexate: reduced excretion of methotrexate (increased risk of toxicity). Notes: Inject at a slow, steady rate to avoid blockage of the needle. Procaine benzylpenicillin is not recommended as first-line treatment for neonatal sepsis except in settings with high neonatal mortality, when given by trained health workers in cases where hospital care is not achievable. Dose equivalence: 1 g = 1 million units. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Cefotaxime ATC code: J01DA10 Powder for injection: 250 mg per vial Indications: Serious infections due to sensitive bacteria, including septicaemia, pneumonia and meningitis; osteomyelitis, septic arthritis; Haemophilus influenzae epiglottis; surgical prophylaxis; prophylaxis of meningococcal meningitis; shigellosis, invasive salmonellosis; endocarditis; gonococcal conjunctivitis; gonorrhoea; pelvic inflammatory disease; Lyme disease. Contraindications: Cefalosporin hypersensitivity. Precautions: Renal impairment; sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction: see section 6.2.1); impaired vitamin K synthesis, low vitamin K stores (chronic disease and malnutrition) as increased risk of bleeding. Dose: Infections due to sensitive Gram-positive and Gram-negative bacteria, surgical prophylaxis, haemophilus epiglottitis and meningitis. IV or IM: Neonate under 7 days 25 mg/kg every 12 hours; Neonate 7–21 days 25 mg/kg every 8 hours; Neonate 21–28 days 25 mg/kg every 6–8 hours. Child 1 month–18 years 50 mg/kg every 8–12 hours, increase to every 6 hours in severe infection and meningitis (maximum 12 g daily). Neonatal doses may be doubled in severe infection and meningitis. Gonorrhoea. IV or IM: Child 1 month–18 years 500 mg as a single dose. ADMINISTRATION IV administration is preferred. Inject IV over 3–5 minutes to avoid arrhythmias. If IM injection is required cefotaxime may be reconstituted with lidocaine 0.5% to 300 mg/ml. Renal impairment: Reduce dose in moderate renal impairment. Hepatic impairment: Dose reduction not necessary. 94 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Adverse effects: Common Diarrhoea, nausea, rash, electrolyte disturbances, pain and inflammation at injection site. Uncommon Vomiting, headache, dizziness, oral and vaginal candidiasis, Clostridium difficile- associated disease, superinfection, eosinophilia, drug fever. Rare Life-threatening arrhythmias with rapid IV administration, anaphylactic shock, bronchial obstruction, urticaria, haemolytic anaemia, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, arthritis, serum sickness-like syndrome, neurotoxicity (including seizures), blood dyscrasias (e.g. neutropenia (related to dose and treatment duration), thrombocytopenia), bleeding, renal impairment. Interactions with other medicines (* indicates severe): Cefalosporins can cause renal impairment; administration with other drugs which also have this effect may increase risk of nephrotoxicity. Aminoglycosides: concomitant cefalosporins and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by one hour. Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Suggestion: allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid vaccine. Notes: Rapid IV administration of large doses may result in seizures, especially if inappropriately high doses are used in renal impairment. Use instead of ceftriaxone for Gram-negative septicaemia in neonates. References: Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ceftazidime ATC code: J01DD02 Powder for injection: 250 mg or 1 g (as pentahydrate) in vial Indications: Infections due to sensitive bacteria, especially those due to Pseudomonas spp. and including those resistant to aminoglycosides. Contraindications: Cefalosporin hypersensitivity (see section 6.2.1). Precautions: Sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction; see section 6.2.1); aztreonam allergy: person may cross-react to ceftazidime; renal impairment; false-positive urinary glucose (if tested for reducing substances) and false-positive Coombs’ test; porphyria. Dose: Infections due to sensitive Gram-positive and Gram-negative bacteria. Deep IM or IV: Neonate under 7 days 25–50 mg/kg every 24 hours; Neonate 7–21 days 25–50 mg/kg every 12 hours; Neonate 21–28 days 25–50 mg/kg every 8 hours. Child 1 month–18 years 25-50 mg/kg every 8 hours (maximum 6 g daily). WHO Model Formulary for Children 2010 95
    • 6 Anti-infective medicines Renal impairment: Reduce dose in mild renal impairment. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Diarrhoea, nausea, rash, electrolyte disturbances, pain and inflammation at injection site, blood dyscrasias (including thrombocytosis, leukopenia and drug-induced eosinophilia), elevations in liver enzymes. Uncommon Vomiting, headache, dizziness, oral and vaginal candidiasis, Clostridium difficile- associated disease, superinfection, drug fever. Rare Anaphylaxis, bronchial obstruction, urticaria, haemolytic anaemia, angioedema, Stevens- Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, arthritis, serum sickness-like syndrome, neurotoxicity (including seizures), blood dyscrasias (including thrombocytopenia and haemolytic anemia), prothrombin time elevations, renal impairment. Interactions with other medicines (* indicates severe): Cefalosporins can cause renal impairment; administration with other drugs which also have this effect may increase risk of nephrotoxicity. Aminoglycosides: concomitant cefalosporins and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by 1 hour. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Suggestion: allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid vaccine. Notes: IV products are physically incompatible with many substances; avoid mixing with other drugs. Carbon dioxide is released during reconstitution; a gas relief needle may be needed to relieve positive pressure. References: Aronson JK, ed. Meyler’s side effects of drugs. 15th ed. Amsterdam, elsevier, 2006. Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. Hansten PD, Horn JH. Drug interactions analysis and management. St Louis, Wolters Kluwer Health, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Imipenem + Cilastatin ATC code: J01DH51 Powder for injection: 250 mg (as monohydrate) + 250 mg (as sodium salt); 500 mg (as monohy- drate) + 500 mg (as sodium salt) in vial Special Notes: Only listed for the treatment of life-threatening hospital-based infection due to suspected or proven multi-resistant infection. Indications: Severe aerobic and anaerobic Gram-positive and Gram-negative infections in hospital (not indicated for CNS infections), including infections caused by resistant Pseudomonas and Acinetobacter spp. Contraindications: Meningitis. 96 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Precautions: Sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction; see also section 6.2.1); renal impairment; CNS disorders, such as epilepsy; neutropenia: drug-related nausea and vomiting is more likely to occur. Dose: Infections due to aerobic and anaerobic Gram-positive and Gram-negative organisms, hospital acquired septicaemia. IV (expressed in terms of imipenem): Neonate under 7 days 20 mg/kg every 12 hours; Neonate 7–21 days 20 mg/kg every 8 hours; Neonate 21–28 days 20 mg/kg every 6 hours. Infant 1–3 months 20 mg/kg every 6 hours. Child 3 months–18 years and under 40 kg 15 mg/kg (maximum 500 mg) every 6 hours; 3 months–18 years and over 40 kg 250–500 mg every 6 hours. Dose may be doubled for less susceptible organisms. ADMINISTRATION Follow manufacturers instructions dependent on product. Caution: complex administration. Reconstitute with 10 ml NaCl 0.9% to form a cloudy suspension. Do not administer this suspension without further dilution. Further dilute to 5 mg/ml with a compatible fluid to give a clear solution. 500 mg or less: over 20–30 minutes. More than 500 mg: over 40–60 minutes. Renal impairment: Reduce dose in mild renal impairment. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nausea, vomiting, diarrhoea, local injection site reactions, e.g. phlebitis. Uncommon Rash, pruritus, urticaria, taste alteration, fever, dizziness, somnolence, confusion, tremor, paraesthesia, headache, psychiatric disturbances, encephalopathy, convulsions (risk of convulsions is higher in people with pre-existing CNS disorders or renal impairment (especially when excessive doses are used). Imipenem is thought to have similar epileptogenic potential to high- dose benzylpenicillin), hypotension, positive Coombs’ test, increases in liver function tests and bilirubin, raised urea and creatinine, Clostridium difficile-associated disease, itch, rash. Rare Red discoloration of the urine in children, anaphylaxis, hepatitis, Stevens-Johnson syndrome, angioedema, tachycardia, renal toxicity, blood dyscrasias. Interactions with other medicines (* indicates severe): Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Suggestion: allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid vaccine. Valproic acid: decreased valproic acid plasma concentrations and loss of anticonvulsant effect. Notes: Suitability of this preparation for intravenous or intramuscular administration varies dependent on product. Check product and instructions carefully. The intramuscular preparation must not be administered intravenously and the infusion preparation must not be administered intramuscularly. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). WHO Model Formulary for Children 2010 97
    • 6 Anti-infective medicines Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 6.2.2 Other antibacterials This section contains a number of antibiotics from different classes which do not fit within other categories but should be available to treat serious infections. They should all be available in centres providing secondary or tertiary level hospital care, and particu- larly in those with intensive care facilities. The use of some of these agents may be restricted by local policy to ensure their cost effective and efficacious use. Azithromycin ATC code: J01FA10 Capsule: 250 mg; 500 mg Oral liquid: 40 mg/ml Indications: Trachoma. Contraindications: Severe hepatic impairment. Precautions: Prolongation of QT interval; renal impairment; hepatic impairment; myasthenia gravis. Dose: Trachoma. Oral: Child all ages 20 mg/kg (maximum 1 g) as a single dose. Renal impairment: Use with caution in patients with severe renal impairment. Hepatic impairment: Mild or moderate hepatic impairment: no modification of dosage is necessary, despite its hepatic metabolism. Severe impairment: avoid; jaundice reported. Adverse effects: Common Gastrointestinal intolerance (nausea, vomiting, diarrhoea, abdominal pain and cramps), headache, candida infections. Uncommon Dizziness, cough, wheeze, dyspnoea, agitation, taste disturbances, rash, fixed drug eruptions. Rare Prolonged QT interval, torsades de pointes, interstitial nephritis, pyloric stenosis, leukopenia, thrombocytopenia, anaphylaxis, acute respiratory distress, Stevens-Johnson syndrome, psychiatric disturbances, hearing loss, seizures, Clostridium difficile-associated disease, pancreatitis, cholestatic jaundice, hepatotoxicity. Interactions with other medicines (* indicates severe): Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of azithromycin. * Artemether with lumefantrine: manufacturer of artemether with lumefantrine advises avoid concomitant use. * Ciclosporin: possible inhibition of metabolism of ciclosporin (increased plasma concentration). 98 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Digoxin: increased plasma concentration of digoxin (increased risk of toxicity). Ritonavir: plasma concentration of azithromycin possibly increased. * Warfarin: possibly enhanced anticoagulant effect of warfarin. Notes: Capsules should be taken at least 1 hour before or 2 hours after food. Mixture should be taken on an empty stomach. Of all the macrolide antibiotics, azithromycin causes the least inhibition of cytochrome P450 3A4. References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Chloramphenicol ATC code: J01BA01 Capsule: 250 mg Oily suspension for injection*: 0.5 g (as sodium succinate)/ml in 2 ml ampoule Oral liquid: 30 mg (as palmitate)/ml Powder for injection: 1 g (sodium succinate) in vial Serious and fatal blood dyscrasias (aplastic anaemia, hypoplastic anaemia, thrombocytopenia and granulocytopenia) have occurred after both short-term and prolonged therapy. Monitor full blood count with platelets frequently in all patients; discontinue if evidence of myelosuppression. Irreversible bone marrow suppression may occur weeks or months after therapy. Avoid repeated courses of treatment. Warn patient or carer to report pale skin, sore throat, fever, tiredness or weakness, or unusual bleeding or bruising in the months after stopping this medicine. Should be reserved for the treatment of life-threatening infections. Grey baby syndrome may follow excessive doses in neonates with immature hepatic metabolism; monitoring of plasma concentrations is required. Special Notes: *Oily suspension for injection is included on the list only for the presumptive treatment of epidemic meningitis in children older than 2 years. In children under 2 years, use ceftriaxone which is approved for use from > 41 weeks corrected gestational age. Some strains of Haemophilus influenzae type b and Salmonella typhi are resistant to chloramphenicol. Indications: Severe life-threatening infections; presumptive treatment of bacterial meningitis in meningococcal epidemic in children older than 2 years. Contraindications: Pregnancy; porphyria; breastfeeding. Precautions: Avoid repeated courses and prolonged use; hepatic impairment; renal impairment; blood counts required before and during treatment; monitor plasma concentrations in neonates (see Warnings); G6PD deficiency. WHO Model Formulary for Children 2010 99
    • 6 Anti-infective medicines Dose: Severe life-threatening infections. IV injection or infusion: Neonate under 2 weeks 12.5 mg/kg every 12 hours. Neonate over 2 weeks 12.5 mg/kg every 6 hours. Oral, IV injection or infusion: Infant or Child 12.5 mg/kg every 6 hours. Maximum daily dose 4 g. Up to 25 mg/kg every 6 hours may be required in severe infections provided plasma concentrations are measured and high doses reduced as soon as possible. THeRAPeUTIC DRUG MONITORING Plasma concentration monitoring required in neonates and high doses; preferred in those under 4 years of age and in hepatic impairment. Recommended peak plasma chloramphenicol concentration (approximately 1 hour after intravenous injection or infusion, or 2 hours after oral administration): 15–25 mg/litre. Pre-dose trough concentration should not exceed 15 mg/litre. Presumptive treatment of bacterial meningitis in meningococcal epidemic. IM injection (using oily injection): Child over 2 years 100 mg/kg as a single dose. Maximum dose 3 g. Renal impairment: Severe: avoid unless no alternative; dose-related depression of haematopoiesis. Hepatic impairment: Avoid if possible; increased risk of bone marrow depression; reduce dose and monitor plasma chloramphenicol concentration. Adverse effects: Common Nausea, vomiting, dry mouth, reversible bone marrow suppression, headache. Uncommon Diarrhoea, glossitis, stomatitis, enterocolitis, mild depression, Clostridium difficile infection, confusion, delirium. Rare Peripheral neuropathy, peripheral neuritis, contact dermatitis, urticaria, angioedema, anaphylaxis, onycholysis, irreversible bone marrow suppression (aplastic anaemia, leukopenia, thrombocytopenia, haemolytic anaemia and leukaemia), hepatotoxicity, optic atrophy, optic neuritis, ototoxicity, bronchospasm, Jarisch-Herxheimer reaction, metabolic acidosis, grey baby syndrome (see below). GRey BABy SyNDROMe Vomiting, greenish diarrhoea, abdominal distension, hypothermia, pallid cyanosis, irregular respiration, circulatory collapse; may follow excessive doses in neonates with immature hepatic metabolism; also reported in infants born to mothers treated in late pregnancy. Interactions with other medicines (* indicates severe): Atazanavir: may increase chloramphenicol serum concentration. Monitor carefully for bone marrow suppression. * Ciclosporin (+ calcineurin inhibitors): plasma concentration of ciclosporin possibly increased. Hydroxocobalamin: response to hydroxocobalamin reduced. Iron: systemic chloramphenicol increases serum iron concentration due to chloramphenicol- induced bone marrow toxicity; if myelosuppression occurs, monitor iron stores and decrease iron dose as needed; consider stopping chloramphenicol, seek specialist advice. Lopinavir + ritonavir: may increase chloramphenicol serum concentration. Monitor carefully for bone marrow suppression. * Phenobarbital: metabolism of chloramphenicol accelerated (reduced chloramphenicol concentration). * Phenytoin: plasma phenytoin concentration increased (increased risk of toxicity). Protease inhibitors: may increase chloramphenicol serum concentration. Monitor carefully for bone marrow suppression. 100 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Rifampicin: accelerated metabolism of chloramphenicol (reduced plasma chloramphenicol concentration). Ritonavir: may increase chloramphenicol serum concentration. Monitor carefully for bone marrow suppression. Saquinavir: may increase chloramphenicol serum concentration. Monitor carefully for bone marrow suppression. * Warfarin: enhanced anticoagulant effect. Notes: Chloramphenicol should be reserved for life-threatening infections including (but not limited to) typhoid fever, septicaemia, meningitis, epiglottitis, pneumonia, cerebral abscess, mastoiditis, rickettsia, listeriosis, Whipple disease, Q fever and psittacosis. Systemic use is limited by its toxicity; if using a high dose, reduce it as soon as possible; avoid repeated courses and prolonged treatment. Obtain complete blood picture before and during treatment (this will not warn of aplastic anaemia); consider stopping treatment if haematological changes occur. Stop treatment if peripheral neuropathy or optic neuritis occur. ReCONSTITUTION AND ADMINISTRATION Reconstitute according to manufacturer’s directions. For intermittent intravenous infusion, dilute reconstituted solution further in glucose 5% or sodium chloride 0.9%. The oily injection is for intramuscular use only (see notes above). References: Aronson JK, ed. Meyler’s side effects of drugs. 15th ed. Amsterdam, elsevier, 2006. Hey e. Neonatal formulary. 4th ed. Oxford, Blackwell Publishing, 2007. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Pocket book of hospital care for children: guidelines for the management of common illnesses with limited resources. Geneva, World Health Organization, 2005. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Standardized treatment of bacterial meningitis in Africa in epidemic and non-epidemic situations. Geneva, World Health Organization, 2007 (http://www.who.int/csr/resources/publications/meningitis/WHO_CDS_ePR_2007_3.pdf, accessed 10 May 2010). Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Ciprofloxacin ATC code: J01MA02 Oral liquid: 50 mg/ml Solution for IV infusion: 2 mg/ml Tablet: 250 mg (as hydrochloride) Achilles tendinitis and tendon rupture have been reported with fluoroquinolones in patients of all ages. Indications: Treatment of infections due to susceptible organisms including Pseudomonas, cholera, shigellosis, Campylobacter, typhoid and gonorrhoea. Local resistance patterns need to taken into account. Contraindications: History of tendon disorders related to quinolone use; pregnancy; breastfeeding. WHO Model Formulary for Children 2010 101
    • 6 Anti-infective medicines Precautions: History of epilepsy; conditions that predispose to seizures; G6PD deficiency; myasthenia gravis; avoid exposure to excessive sunlight (discontinue if photosensitivity occurs); tendon damage; renal impairment; avoid excessive alkalinity of urine and ensure adequate fluid intake as risk of crystalluria. The drug should be discontinued if psychiatric, neurological or hypersensitivity reactions, including severe rash, occur. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. TeNDON DAMAGe Tendon damage (including rupture) has been reported rarely in patients receiving quinolones. Tendon rupture may occur within 48 hours of starting treatment. Health-care workers should be aware that the risk of tendon rupture is increased by the concomitant use of corticosteroids; if tendinitis is suspected, the quinolone should be discontinued immediately. Dose: Complicated urinary tract infection. Oral: Neonate 7.5 mg/kg twice daily. Infant 5–7.5 mg/kg twice daily. Dose may be doubled in severe infection. Child 10 mg/kg twice daily. Dose may be doubled in severe infections. Maximum dose 750 mg twice daily. IV infusion: Neonate 5 mg/kg every 12 hours. Infant 4 mg/kg every 12 hours. Dose may be doubled in severe infections. Child 6 mg/kg every 8 hours, increased to 10 mg/kg every 8 hours in severe infections. Maximum dose 400 mg every 8 hours. Severe respiratory tract infections, gastrointestinal infections. Oral: Neonate 7.5 mg/kg twice daily. Infant 5–7.5 mg/kg twice daily. Dose may be doubled in severe infections. Child 20 mg/kg twice daily. Maximum dose 750 mg twice daily. IV infusion: Neonate 5 mg/kg every 12 hours. Infant 4 mg/kg every 12 hours. Dose may be doubled in severe infections. Child 10 mg/kg every 8 hours. Maximum dose 400 mg every 8 hours. Pseudomonal lower respiratory tract infection in cystic fibrosis. Oral: Infant 15 mg/kg twice daily. Child 20 mg/kg twice daily. Maximum dose 750 mg twice daily. IV: Infant 4–8 mg/kg every 12 hours. Child 10 mg/kg every 8 hours. Maximum dose 400 mg every 8 hours. Treatment and post-exposure prophylaxis of anthrax. Oral: Infant or Child 15 mg/kg twice daily. Maximum 500 mg twice daily. IV: Infant or Child 10 mg/kg every 12 hours. Maximum 400 mg per dose. NOTe Cutaneous anthrax should be treated for 7 days, inhalational or gastrointestinal should be treated for 60 days. Post-exposure prophylaxis should be administered for 60 days. Other antibiotics may be used if and when sensitivities are known. 102 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Renal impairment: Reduce dose if CrCl < 30 ml/minute. Adverse effects: Common Rash, itch, gastrointestinal intolerance (nausea, vomiting, dyspepsia, diarrhoea, abdominal pain), metallic taste. Uncommon Headache, dizziness, insomnia, depression, restlessness, tremors, arthralgia, arthritis, myalgia, tendinitis, raised liver enzymes, erythema, pain or thrombophlebitis at intravenous infusion site. Rare Interstitial nephritis, blood dyscrasias (including agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, methaemoglobinaemia, pancytopenia and thrombocytopenia), orofacial dyskinesia, disturbances in vision, transient hearing impairment, movement disorders, seizures, psychotic reactions, peripheral oedema, angioedema, anaphylaxis, Clostridium difficile infection, tendon inflammation and rupture, vasculitis, crystalluria, renal failure, pancreatitis, hepatitis, cholestatic jaundice, peripheral neuropathy, photosensitivity, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, Jarisch-Herxheimer reaction, hyperglycaemia, blood coagulation disorder. Interactions with other medicines (* indicates severe): Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of ciprofloxacin. * Artemether + lumefantrine: manufacturer of artemether with lumefantrine advises to avoid concomitant use. Calcium salts: reduced absorption of ciprofloxacin. * Ciclosporin: increased risk of nephrotoxicity. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Dairy products: reduced absorption of ciprofloxacin. Ferrous salts: absorption of ciprofloxacin reduced by oral ferrous salts. * Ibuprofen: possibly increased risk of seizures. Methotrexate: increased methotrexate concentration and risk of toxicity when high-dose methotrexate is given; monitor methotrexate concentration carefully as increased rescue treatment with calcium folinate may be needed. Morphine: manufacturer of ciprofloxacin advises to avoid premedication with morphine (reduced plasma ciprofloxacin concentration) when ciprofloxacin used for surgical prophylaxis. Phenytoin: plasma phenytoin concentration can be increased or decreased by ciprofloxacin. Theophylline: may result in increased plasma levels of theophylline and significant adverse effects. Thyroid hormones: ciprofloxacin may interfere with absorption of thyroxine, resulting in hypothyroidism; separate drug administration times during a long ciprofloxacin course, and monitor thyroid function. * Warfarin: enhanced anticoagulant effect. Zinc sulfate: reduced absorption of ciprofloxacin. Notes: Best taken on an empty stomach. Separate doses from iron, antacids and milk by 2 hours. Important to maintain an adequate fluid intake. Consider the necessity for intravenous administration as adequate levels can be achieved using oral formulations due to high bioavailability. Can cause photosensitivity. Use sunscreen, wear protective clothing and a hat. ADMINISTRATION For intravenous administration, administer by slow intravenous infusion over 60 minutes. Final concentration for administration should not exceed 2 mg/ml. WHO Model Formulary for Children 2010 103
    • 6 Anti-infective medicines References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Doxycycline ATC code: J01AA02 Oral liquid: 5 mg/ml; 10 mg/ml Solid oral dosage form: 50 mg; 100 mg (hydrochloride) Special Notes: WHO age/weight restriction: > 8 years (except for serious infections, e.g. cholera). Indications: Bacterial infections. Contraindications: Pregnancy; breastfeeding; porphyria; systemic lupus erythematosus. Precautions: Children under 8 years (avoid unless life-threatening infection when no other alternative exists); avoid exposure to sunlight or sunlamps (photosensitivity reported); renal impairment; hepatic impairment; concomitant hepatotoxic drugs; myasthenia gravis. Dose: Bacterial infections. Oral: Child over 8 years 2 mg/kg (maximum 100 mg) twice daily on day 1, then 2 mg/kg (maximum 100 mg) daily, or twice daily in severe infections such as rickettsia. Maximum daily dose 200 mg. Renal impairment: Use with caution; avoid excessive doses. Hepatic impairment: Avoid (or use with caution). Adverse effects: Common Gastrointestinal intolerance (nausea, vomiting, diarrhoea, epigastric burning), tooth discoloration (permanent in children aged < 8 years), enamel dysplasia, reduced bone growth (in children < 8 years), photosensitivity (depends on dose and degree of sun exposure). Uncommon Rash, stomatitis, bone deformity, fungal overgrowth. Rare Photo-onycholysis and nail discoloration, oesophageal ulcers (due to partly swallowed tablets or capsules), antibiotic-associated colitis (Clostridium difficile-associated disease), hepatitis, fatty liver degeneration (with high doses, especially in pregnancy), pancreatitis, hepatotoxicity, headache and visual disturbances may indicate benign intracranial hypertension, bulging fontanelles in infants, allergic reactions including anaphylaxis (less common than with penicillins), toxic epidermal necrolysis, worsening of systemic lupus erythematosus, serum sickness-like reactions, Jarisch- Herxheimer reaction when treating spirochetal infections. Interactions with other medicines (* indicates severe): Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of doxycycline. Carbamazepine: accelerated metabolism of doxycycline (reduced effect). * Ciclosporin: possibly increased plasma ciclosporin concentration. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Ferrous salts: absorption of oral ferrous salts reduced by doxycycline; absorption of doxycycline reduced by oral ferrous salts. 104 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Methotrexate: increased risk of methotrexate toxicity. Phenobarbital: metabolism of doxycycline accelerated (reduced plasma concentration). Phenytoin: increased metabolism of doxycycline (reduced plasma concentration). Rifampicin: plasma doxycycline concentration possibly reduced. * Warfarin: anticoagulant effect possibly enhanced. Notes: Separate dose from antacids and iron supplements by 2 hours. Swallow whole with plenty of water and remain upright (do not lie down) for an hour after taking doxycycline to prevent oesophageal irritation. Single daily doses are best taken in the morning rather than at night. References: eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Erythromycin ATC code: J01FA01 Powder for oral liquid: 25 mg/ml (as stearate or ethyl succinate) Solid oral dosage form: 250 mg (as stearate or ethyl succinate) Indications: Treatment of susceptible infections as an alternative to penicillin in hypersensitive patients; treatment of susceptible infections such as Campylobacter enteritis, cholera, oral infections, respiratory tract infections (including pneumonia, legionnaires’ disease, streptococcal pharyngitis) and diphtheria; prevention of secondary case of diphtheria and pertussis in non- immune patients. Contraindications: Hypersensitivity to erythromycin or other macrolides; porphyria; severe hepatic impairment; treatment with cisapride. Precautions: Hepatic impairment; renal impairment; predisposition to QT interval prolongation; neonates under 2 weeks; porphyria. Dose: Treatment of susceptible infections. Oral: Neonate 12.5 mg/kg every 6 hours. Infant or Child under 2 years 125 mg every 6 hours, doubled in severe infections; 2–8 years 250 mg every 6 hours, doubled in severe infections; over 8 years 250–500 mg every 6 hours, doubled in severe infections. Prevention of secondary case of diphtheria in non-immune patient. Oral: Infant or Child under 2 years 125 mg every 6 hours for 7 days; 2–8 years 250 mg every 6 hours for 7 days; over 8 years 500 mg every 6 hours for 7 days. Treat for a further 10 days if nasopharyngeal swabs are positive after first 7 days of treatment. Prevention of secondary case of pertussis in non-immune patient. Oral: Infant or Child under 2 years 125 mg every 6 hours for 7 days; 2–8 years 250 mg every 6 hours for 7 days; over 8 years 500 mg every 6 hours for 7 days. WHO Model Formulary for Children 2010 105
    • 6 Anti-infective medicines Renal impairment: Severe impairment: reduce dose. Risk of ototoxicity. Hepatic impairment: May cause idiosyncratic hepatotoxicity. Mild to moderate impairment: use with caution; hepatic impairment may worsen. Severe impairment: avoid use. Adverse effects: Common Gastrointestinal intolerance (nausea, vomiting, abdominal discomfort, diarrhoea), headache, dyspnoea, cough, candidal infections, phlebitis, infantile hypertrophic pyloric stenosis (see below). Uncommon Rash, fixed drug eruptions, urticaria, reversible hearing loss after large doses. Rare Myasthenia-like syndrome, anaphylaxis, acute respiratory distress, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psychiatric disturbances, hearing loss, seizures, Clostridium difficile infection, cholestatic jaundice, pancreatitis, prolonged QT interval, torsades de pointes. INFANTILe HyPeRTROPHIC PyLORIC STeNOSIS Has occurred in about 5% of a cohort of infants receiving erythromycin for pertussis prophylaxis; risk increased with increasing length of treatment; no increased risk in infants receiving erythromycin after 2 weeks of age. Interactions with other medicines (* indicates severe): erythromycin has multiple drug-drug interactions as it is a potent inhibitor of cytochrome P450 3A4 and 1A2. * Artemether + lumefantrine: manufacturer of artemether with lumefantrine advises avoid concomitant use. * Carbamazepine: increased plasma carbamazepine concentration. * Ciclosporin: increased plasma ciclosporin concentration (inhibition of metabolism of ciclosporin). Dexamethasone: erythromycin possibly inhibits metabolism of dexamethasone. Digoxin: increased plasma concentration of digoxin (increased risk of toxicity). Hydrocortisone: erythromycin possibly inhibits metabolism of hydrocortisone. Prednisolone: erythromycin possibly inhibits metabolism of prednisolone. * Quinidine: increased risk of ventricular arrhythmias with parenteral erythromycin. Ritonavir: plasma concentration possibly increased by ritonavir. * Theophylline: may increase theophylline concentration and toxicity; erythromycin levels may concurrently decrease, possibly affecting its efficacy. Valproic acid: metabolism of valproic acid possibly inhibited (increased plasma concentration). * Verapamil: increased risk of cardiotoxicity and serious prolongation of QT interval. * Vinblastine: increased toxicity of vinblastine (avoid concomitant use). * Warfarin: enhanced anticoagulant effect. Notes: Total oral daily dose may be halved and given every 12 hours, however diarrhoea is a common side effect. Stop erythromycin if severe hepatic dysfunction develops. The ethyl succinate (eeS) salt is given without regard to food. The base and stearate salt are given on an empty stomach 1 hour before or 2 hours after meals. Parents of neonates: tell your doctor if your baby develops vomiting or is irritable when feeding while taking erythromycin. Warn patients or carers that erythromycin interacts with many drugs and even herbal products so inform doctor or pharmacist before taking additional medication. 106 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Gentamicin ATC code: J01GB03 Injection: 10 mg; 40 mg (as sulfate)/ml in 2 ml vial Aminoglycosides are associated with significant nephrotoxicity; vestibular and permanent bilateral auditory ototoxicity can occur; tinnitus or vertigo are indications of vestibular injury and impending bilateral irreversible deafness. Risk of nephrotoxicity and ototoxicity is increased in patients with impaired renal function, high-dose therapy or prolonged therapy. Risk of nephrotoxicity increases when used concurrently with other potentially nephrotoxic drugs; renal damage is usually reversible. Risk of ototoxicity increases with use of potent diuretics. Special Notes: This medicine is listed as a representative of its pharmacological class. Other medicines in the same class may have similar clinical performance and may be selected for local formularies based on availability and price. The information in this monograph only applies to the medicine listed here. Indications: Treatment of infections with susceptible organisms taking local resistance factors into account, including septicaemia, pneumonia, acute pyelonephritis and meningitis. Contraindications: Myasthenia gravis. Precautions: Renal impairment; neonates and infants (use with caution and monitor renal, auditory and vestibular function, and serum gentamicin concentrations); avoid prolonged use; conditions characterized by muscular weakness; obesity (use ideal body weight to calculate dose and monitor serum gentamicin concentration closely). Dose: Treatment of infections with susceptible organisms. IV or IM: Term neonate 3.5–5 mg/kg once daily. Infant or Child under 10 years 7.5 mg/kg once daily; over 10 years 6 mg/kg once daily (maximum dose 240–360 mg). THeRAPeUTIC DRUG MONITORING Monitor serum gentamicin concentration and reduce doses or increase dosing intervals, or both, as necessary. Pre-dose (“trough”) concentration should be less than 1 mg/litre. Renal impairment: Reduce dose frequency. Monitor renal, auditory and vestibular function. Monitor serum gentamicin concentration. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nephrotoxicity (see below), ototoxicity (see below). Rare Hypomagnesaemia, hypokalaemia, hypocalcaemia, anaphylaxis (probably due to sulfites in some formulations), bronchospasm, neuromuscular blockade (see below), oliguria, peripheral neuropathy, antibiotic-associated colitis. WHO Model Formulary for Children 2010 107
    • 6 Anti-infective medicines NePHROTOXICITy Usually reversible and can be anticipated if treatment lasts > 7–10 days; usually presents as gradually worsening non-oliguric renal failure with increasing serum creatinine and proteinuria, but may present as acute tubular necrosis. OTOTOXICITy Clinically evident vestibular ototoxicity (nausea, vomiting, vertigo, nystagmus, difficulties with gait) and cochlear ototoxicity (noticeable hearing loss, tinnitus, feeling of fullness in ear) have been associated with gentamicin use. As the patient is unaware of the first symptoms of cochlear toxicity, it may appear to begin after stopping treatment. Ototoxicity caused by gentamicin can be irreversible; permanent deafness may occur. NeUROMUSCULAR BLOCKADe May result in respiratory depression; can usually be reversed with prompt administration of IV calcium gluconate; the effect of neostigmine is variable. Interactions with other medicines (* indicates severe): Amphotericin B: increased risk of nephrotoxicity. Capreomycin: increased risk of nephrotoxicity and ototoxicity. * Ciclosporin: increased risk of nephrotoxicity. Digoxin: possibly increased plasma concentration of digoxin. * Furosemide: increased risk of ototoxicity. Magnesium sulfate: additive neuromuscular blocking effect with aminoglycosides and parenteral magnesium sulfate; use combinations cautiously, monitor respiratory function. * Neostigmine: antagonism of effect of neostigmine. Nondepolasing neuromuscular blockers: aminoglycosides prolong effect of nondepolarising neuromuscular blockers; may lead to respiratory insufficiency. Other nephrotoxic agents: co-administration with other drugs which are ototoxic or nephrotoxic may increase risk of these adverse effects. Penicillins: concomitant penicillin and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by 1 hour. * Pyridostigmine: antagonism of effect of pyridostigmine. * Suxamethonium: enhanced muscle relaxant effect. Vancomycin: increased risk of nephrotoxicity and ototoxicity. * Vecuronium: enhanced muscle relaxant effect. Notes: In obese or severely oedematous children use the ideal weight for height to calculate dose. ADMINISTRATION For intravenous infusion, dilute in glucose 5% or sodium chloride 0.9%; infuse over 30–60 minutes. Final concentration of intravenous administration should not exceed 10 mg/ml. Administer other antibiotics, such as cefalosporins and penicillins, at least 1 hour before or after gentamicin. Target serum concentrations may vary depending on indication and institution. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 108 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Metronidazole ATC code: J01XD01 Injection: 500 mg in 100 ml vial Oral liquid: 40 mg (as benzoate)/ml Tablet: 200 mg to 500 mg Indications: Anaerobic bacterial infections including ulcerative gingivitis, acute oral infections, tetanus, skin and soft tissue infections, and Clostridium difficile infection (oral therapy); surgical prophylaxis. Precautions: Hepatic impairment; disulfiram-like reaction with alcohol; clinical and laboratory monitoring in courses lasting longer than 10 days. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Anaerobic bacterial infections. Oral: Neonate initially 15 mg/kg then 7.5 mg/kg every 12 hours. Infant or Child 7.5 mg/kg every 8 hours. Maximum dose 400 mg. IV infusion: Neonate 15 mg/kg as a single loading dose, followed by 7.5 mg/kg every 12 hours starting 24 hours after loading dose. Infant or Child 7.5 mg/kg every 8 hours. Maximum dose 500 mg. NOTe Acute ulcerative gingivitis is usually successfully treated in 3 days, Clostridium difficile infection should be treated orally, and is usually treated for 7–10 days, while other anaerobic and oral anaerobic conditions usually treated for only 7 days. Surgical prophylaxis. Oral or IV infusion: Infant or Child 7.5 mg/kg 2 hours before surgery. Up to 3 further doses of 7.5 mg/kg may be given every 8 hours for high-risk procedures. Maximum dose 500 mg. Renal impairment: Metabolites may accumulate in severe impairment possibly causing adverse effects. Dose adjustment is not usually necessary. Hepatic impairment: Severe impairment: reduce total daily dose to one third and give once daily. Use with caution in hepatic encephalopathy. Adverse effects: Common Gastrointestinal intolerance (nausea, abdominal pain, vomiting, diarrhoea), anorexia, metallic taste, CNS effects (e.g. dizziness, headache), thrombophlebitis (IV). Uncommon Furry tongue, glossitis, stomatitis, paraesthesia. Rare Pancreatitis, abnormal liver function tests, jaundice, hepatitis, optic neuritis, thrombocytopenia, Clostridium difficile-associated disease, hypersensitivity reactions (e.g. rash, itch, flushing, fever), anaphylaxis, angioedema, erythema multiforme, Stevens-Johnson syndrome, leukopenia, peripheral neuropathy, seizures, darkening of the urine. HIGH-DOSe AND/OR PROLONGeD TReATMeNT Leukopenia is reversible and usually only occurs after prolonged treatment; peripheral neuropathy (usually reversible) and/or CNS toxicity (including seizures) may occur. Interactions with other medicines (* indicates severe): Alcohol: disulfiram-like reaction. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Fluorouracil: metabolism of fluorouracil inhibited (increased toxicity). WHO Model Formulary for Children 2010 109
    • 6 Anti-infective medicines Lithium: increased lithium toxicity reported. Lopinavir liquid: disulfuram-like reaction. Phenobarbital: metabolism of metronidazole accelerated (reduced plasma concentration). * Phenytoin: metabolism of phenytoin inhibited (increased plasma phenytoin concentration). * Warfarin: enhanced anticoagulant effect. Notes: Well absorbed orally and the intravenous route is normally reserved for severe infections. Oral absorption from the suspension is lower than from the tablets. Patients should be advised to swallow tablets whole with water, during or after food; suspension is best taken 1 hour before food (or on an empty stomach). ADMINISTRATION For intravenous infusion, infuse over 20–30 minutes. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Nitrofurantoin ATC code: J01Xe01 Oral liquid: 5 mg/ml Tablet: 100 mg Indications: Treatment of acute uncomplicated urinary tract infection; prophylaxis of urinary tract infection. Contraindications: Renal impairment; infants less than 3 months; G6PD deficiency; pregnancy, at term; porphyria. Precautions: Pulmonary disease; hepatic impairment; monitor lung and liver function on long- term therapy (discontinue if lung function deteriorates); electrolyte imbalance; susceptibility to peripheral nephritis; anaemia; diabetes mellitus; vitamin B and folate deficiency; false-positive urinary glucose (if testing for reducing substances); urine may be coloured yellow or brown. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Treatment of acute uncomplicated urinary tract infection. Oral: Infant or Child over 3 months 750 micrograms/kg four times daily for 3–7 days. Maximum dose 100 mg. Prophylaxis of urinary tract infection. Oral: Infant or Child over 3 months 1 mg/kg at night. Maximum dose 100 mg. Renal impairment: Avoid in all degrees of renal impairment. Risk of peripheral neuropathy. Treatment may be ineffective because of inadequate urine concentrations. Hepatic impairment: Cholestatic jaundice and chronic active hepatitis reported. 110 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Adverse effects: Common Dose related gastrointestinal disorders (including nausea and vomiting, anorexia, diarrhoea and abdominal pain), hypersensitivity reactions (including urticaria, rash, sialadenitis, pruritus, angioedema), headache. Uncommon Drowsiness, vertigo, dizziness. Rare Peripheral polyneuropathy (see below), cholestatic jaundice, hepatitis, hepatotoxicity (see below), acute and chronic pulmonary reactions (see below), skin reactions including erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, lupus-like syndrome, anaphylaxis, drug fever, blood disorders including eosinophilia, arthralgia, pancreatitis, benign intracranial hypertension. HePATOTOXICITy Acute hepatocellular or cholestatic reactions generally occur in the first 6 weeks of treatment, sometimes with fever, eosinophilia, rash and are usually reversible. Chronic active hepatitis (sometimes reversible) mostly occurs in women, usually after about 6 months treatment; may be associated with pulmonary toxicity (see below). Both types can be fatal. PULMONARy TOXICITy Pulmonary fibrosis has been reported. Possible association with lupus erythematosus-like syndrome. PeRIPHeRAL POLyNeUROPATHy Begins with peripheral paraesthesia and sensory loss (usually in lower limbs); can progress to motor loss and muscle atrophy. Improvement usually occurs after stopping treatment, but it may be incomplete. The main predisposing factor appears to be renal impairment. Interactions with other medicines (* indicates severe): Fluconazole: concurrent use may result in increased risk of hepatic and pulmonary toxicity. Norfloxacin: may result in antagonism of the antibacterial effect of norfloxacin. Folic acid: concurrent use may result in decreased folic acid serum levels. Notes: Give with food or milk to reduce nausea and to improve absorption. PATIeNT ADVICe Patients and their carers should be advised to tell their doctor immediately if they have difficulty breathing, develop a cough or get any numbness or tingling. MONITORING During long-term treatment monitor the following: pulmonary function; liver function every month for 3 months, then every 3 months, as onset of hepatotoxicity may be insidious; renal function as peripheral polyneuropathy is more likely to occur if this is impaired; for development of paraesthesia as stopping treatment early can prevent severe neuropathy. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Sulfamethoxazole + Trimethoprim ATC code: J01ee01 Injection: 80 mg + 16 mg/ml in 5 ml ampoule; 80 mg + 16 mg/ml in 10 ml ampoule Oral liquid: 40 mg + 8 mg/ml Tablet: 100 mg + 20 mg; 400 mg + 80 mg Special Notes: Also referred to as co-trimoxazole. Indications: Treatment of infections with susceptible organisms including urinary tract infections, respiratory tract infection, typhoid fever and otitis media. Local antimicrobial patterns need to be taken into account. WHO Model Formulary for Children 2010 111
    • 6 Anti-infective medicines Contraindications: Hypersensitivity to sulfonamides or trimethoprim; porphyria; megaloblastic anaemia; severe renal impairment; severe hepatic impairment. Precautions: Mild to moderate renal impairment; maintain adequate fluid intake (to avoid crystalluria); avoid in blood disorders (unless under specialist supervision); monitor blood counts on prolonged treatment; discontinue immediately if blood disorder develops; rash (discontinue immediately); predisposition to folate deficiency; asthma; G6PD deficiency; avoid in infants under 6 weeks. Dose: Doses are expressed in terms of the trimethoprim component. Treatment of infections with susceptible organisms. Oral: Infant or Child over 6 weeks 4 mg/kg/dose twice daily. Maximum 160 mg twice daily. IV infusion: Infant or Child over 6 weeks 3 mg/kg every 12 hours. Maximum 160 mg twice daily. Renal impairment: Severe impairment: avoid use. Moderate impairment: use half normal dose. Plasma monitoring may be required with high doses in renal impairment; seek expert advice. Hepatic impairment: Severe impairment: avoid use. Adverse effects: Some adverse effects may be hypersensitivity reactions (see below). Incidence of some adverse effects (rash, fever, nausea, neutropenia, thrombocytopenia, raised hepatic aminotransferases) is substantially higher in patients with AIDS. Common Fever, nausea, vomiting, diarrhoea, anorexia, rash, itch, stomatitis, hyperkalaemia, thrombocytopenia, photosensitivity. Uncommon Headache, drowsiness, hyperkalaemia, blood disorders (including neutropenia, leukopenia, thrombocytopenia, eosinophilia, megaloblastic anaemia, methaemoglobinaemia). Rare erythema, vasculitis, hyponatraemia, hypoglycaemia, pancreatitis, hepatitis, jaundice, hepatic necrosis, crystalluria, urinary obstruction with anuria/oliguria, lowered mental acuity, depression, tremor, ataxia (after IV use in HIV patients), nephrotoxicity, antibiotic-associated colitis, Clostridium difficile-associated disease, aseptic meningitis. HyPeRSeNSITIVITy May present with fever, dyspnoea, cough, rash, eosinophilia; the most serious effects include anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, serum sickness-like syndrome, lupus- like syndrome, pneumonitis, hepatitis, interstitial nephritis, systemic vasculitis and pancytopenia. Interactions with other medicines (* indicates severe): Trimethoprim is a folate antagonist and will add to the effects on bone marrow of other folate antagonists, e.g. pyrimethamine. Trimethoprim can cause hyperkalaemia; administration with potassium supplements or other drugs which also cause potassium retention can further increase potassium concentration. Trimethoprim with sulfamethoxazole can cause nephrotoxicity; giving with other nephrotoxic drugs may cause additional renal adverse effects. * Azathioprine: increased risk of haematological toxicity. * Ciclosporin: increased risk of nephrotoxicity; plasma ciclosporin concentration possibly reduced by intravenous trimethoprim. Dapsone: plasma concentration of both dapsone and trimethoprim may increase with concomitant use. Digoxin: plasma concentration of digoxin possibly increased. Lamivudine: competes for renal excretion, increasing lamivudine concentration and risk of toxicity. * Mercaptopurine: increased risk of haematological toxicity. 112 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials * Methotrexate: antifolate effect of methotrexate increased (avoid concomitant use). * Phenytoin: antifolate effect and plasma phenytoin concentration increased. * Pyrimethamine: increased antifolate effect. Rifampicin: decreases concentrations of trimethoprim and sulfamethoxazole when used for prophylaxis in HIV-positive patients, decreasing its efficacy. * Sulfadoxine + pyrimethamine: increased antifolate effect. Warfarin: possibly enhanced anticoagulant effect. Notes: Oral dose is best given with or after food. Attention should be paid to the folate status of the patient should treatment be prolonged or high dose. DILUTION AND ADMINISTRATION For intermittent intravenous infusion may be further diluted in glucose 5% and 10% or sodium chloride 0.9% or Ringer’s intravenous solution. Must be further diluted; dilute each 5 ml of injection solution to 125 ml. Infuse over 60–90 minutes (but may be adjusted according to fluid requirements). If fluid restriction necessary, 5 ml may be diluted with 75 ml of glucose 5% and the required dose infused over a maximum of 60 minutes. Check container for haze or precipitant during administration. In severe fluid restriction may be given undiluted via a central venous line. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Trimethoprim ATC code: J01eA01 Oral liquid: 10 mg/ml Tablet: 100 mg; 200 mg Special Notes: WHO age/weight restriction: > 6 months. Indications: Treatment of urinary tract infection and respiratory tract infection; prophylaxis of urinary tract infection. Contraindications: Blood disorders including megaloblastic anaemia due to folate deficiency; severe renal impairment. Precautions: Mild to moderate renal impairment; hepatic impairment; predisposition to folate deficiency; blood counts on long-term therapy; porphyria; neonates and infants < 6 months. BLOOD DISORDeRS On long-term treatment, patients and their carers should be told how to recognize signs of blood disorders and advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, purpura, bruising or bleeding develop. Dose: Treatment of urinary tract infection and respiratory tract infection. Oral: Infant or Child over 6 months 4 mg/kg twice daily. Maximum 200 mg twice daily. Prophylaxis of urinary tract infection. Oral: Infant or Child over 6 months 2 mg/kg (maximum 100 mg) at night. WHO Model Formulary for Children 2010 113
    • 6 Anti-infective medicines Renal impairment: Mild to moderate impairment: use half normal dose if CrCl 15–30 ml/minute. Moderate to severe impairment: avoid use if CrCl less than 15 ml/minute. Hepatic impairment: Use with caution. Dose reduction not required. Adverse effects: Common Fever, pruritus, rash, nausea, vomiting, glossitis, hyperkalaemia (see below), superinfection (Candida species). Uncommon Sore mouth, increase in serum creatinine. Rare Leukopenia, thrombocytopenia, megaloblastic anaemia, methaemoglobinaemia (especially with high doses or prolonged treatment), allergy including anaphylaxis, erythema multiforme (Stevens- Johnson syndrome), toxic epidermal necrolysis, aseptic meningitis. HyPeRKALAeMIA Trimethoprim causes potassium retention. Hyperkalaemia can occur with usual doses but is more likely to be clinically significant as dose increases. Average onset is 4–5 days. Risk factors are high doses, renal impairment and use of other potassium-retaining drugs (see Interactions). Interactions with other medicines (* indicates severe): Trimethoprim is a folate antagonist and will add to the effects on bone marrow of other folate antagonists, e.g. pyrimethamine. * Azathioprine: increased risk of haematological toxicity. * Ciclosporin: increased risk of nephrotoxicity; plasma ciclosporin concentration possibly reduced by intravenous trimethoprim. Dapsone: plasma concentration of both dapsone and trimethoprim may increase with concomitant use. Digoxin: plasma concentration of digoxin possibly increased. Enalapril: increased risk of hyperkalaemia. Lamivudine: competes for renal excretion, increasing lamivudine concentration and risk of toxicity. * Mercaptopurine: increased risk of haematological toxicity. * Methotrexate: antifolate effect of methotrexate increased (avoid concomitant use). * Phenytoin: antifolate effect and plasma phenytoin concentration increased. * Pyrimethamine: increased antifolate effect. * Sulfadoxine + pyrimethamine: increased antifolate effect. Warfarin: possibly enhanced anticoagulant effect. Notes: Monitor complete blood picture and folate status during prolonged or high-dose treatment. Monitor serum potassium, beginning on day 3, if the patient has renal impairment, is taking drugs which can cause hyperkalaemia or is taking a high dose. Give at night to maximize urinary concentration for urinary tract infection prophylaxis. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 114 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Clindamycin ATC code: J01FF01 Capsule: 150 mg Injection: 150 mg (as phosphate)/ml Oral liquid: 15 mg/ml Antibiotic-associated colitis (Clostridium difficile infection) may be fatal, discontinue treatment immediately if diarrhoea develops. Special Notes: Clindamycin is a complementary drug when penicillin is not appropriate. Indications: Treatment of infections with susceptible organisms where allergy to penicillin and resistance to first-line drugs, including staphylococcal bone and joint infections, peritonitis and pneumonia. Contraindications: Diarrhoeal states; avoid injections containing benzyl alcohol in neonates; porphyria. Precautions: Discontinue immediately if diarrhoea or colitis develop; hepatic impairment; renal impairment; monitor liver and renal function on prolonged therapy and in neonates and infants; females; avoid rapid intravenous administration; avoid taking with antidiarrhoeal medication. Dose: Treatment of infections with susceptible organisms where allergy to penicillin and resistance to first-line drugs. Oral: Neonate under 14 days 3–6 mg/kg three times daily; Neonate 14–28 days 3–6 mg/kg four times daily. Infant or Child 3–6 mg/kg four times daily (body weight under 10 kg, minimum dose 37.5 mg three times daily). Maximum dose 450 mg four times daily. IV infusion or deep IM injection: Infant or Child 3.75–6.25 mg/kg four times daily; increased up to 10 mg/kg four times daily in severe infections. Total daily dose may alternatively be given in three divided doses. In life- threatening infection, up to 1.2 g four times daily may be used. Single doses over 600 mg must be given by intravenous infusion. Renal impairment: Severe impairment: reduce dose. Hepatic impairment: Severe impairment: reduce dose. Adverse effects: Common Diarrhoea (mild to severe: discontinue treatment), nausea, vomiting, abdominal discomfort, rash, pruritus, urticaria. Uncommon Antibiotic-associated colitis (Clostridium difficile infection). Rare Taste disturbance, oesophagitis, anaphylaxis (often related to the tartrazine in the capsule preparation), blood dyscrasias (neutropenia, eosinophilia, agranulocytosis and thrombocytopenia), polyarthritis, jaundice and altered liver function tests, hepatotoxicity (with high doses), Stevens- Johnson syndrome, exfoliative and vesiculobullous dermatitis, toxic epidermal necrolysis (“slow” red man syndrome). IV Hypotension, cardiac arrest (rapid injection), thrombophlebitis. IM Pain, induration, sterile abscess. Interactions with other medicines (* indicates severe): Neostigmine: antagonism of effects of neostigmine. Pyridostigmine: antagonism of effects of pyridostigmine. WHO Model Formulary for Children 2010 115
    • 6 Anti-infective medicines * Suxamethonium: enhanced effects of suxamethonium. * Vecuronium: enhanced muscle relaxant effect. Notes: Consider the necessity for IV administration as adequate levels can be achieved using oral formulations due to high bioavailability. PATIeNT ADVICe Patients should discontinue immediately and contact doctor if diarrhoea develops; capsules should be swallowed with a glass of water. ADMINISTRATION ADVICe For intravenous infusion, dilute in glucose 5% or sodium chloride 0.9% to concentration not > 12 mg/ml and infuse slowly IV over 30–40 minutes to reduce risk of adverse cardiac effects (hypotension, cardiac arrest). References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Vancomycin ATC code: J01XA01 Powder for injection: 250 mg (as hydrochloride) in vial Special Notes: Vancomycin is a complementary antibacterial drug for use only when there is significant resistance to other drugs on the WHO Model List of essential Medicines for Children. Indications: Treatment of infections with susceptible organisms including methicillin-resistant staphylococcal pneumonia, staphylococcal meningitis, antibiotic-associated colitis, endocarditis treatment and prophylaxis. Local antimicrobial patterns need to be taken into account. Contraindications: History of deafness. Precautions: Avoid rapid infusion (risk of anaphylactoid reactions, see Adverse effects); rotate infusion sites; renal impairment; monitor plasma vancomycin concentration (after three or four doses in normal renal function, earlier if renal impairment), blood counts, urine analysis and renal function tests: use only in hospital setting; monitor auditory function and plasma vancomycin concentrations in renal impairment. Dose: Treatment of infections with susceptible organisms. IV infusion: Neonate, Infant or Child 15 mg/kg every 8 hours, adjusted according to plasma concentration. Maximum daily dose 2 g. THeRAPeUTIC DRUG MONITORING Plasma concentration monitoring required; pre-dose (trough) concentration should be 10–15 mg/litre (15–20 mg/litre for less sensitive strains of methicillin-resistant Staphylococcus aureus). Antibiotic-associated colitis. Oral (using the injection solution): Infant or Child under 5 years 5 mg/kg four times daily for 7–10 days; 5–12 years 62.5 mg four times daily for 7–10 days. 116 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Renal impairment: Increase dose interval or reduce dose, or both, in renal impairment. Monitor plasma vancomycin concentration and renal function regularly. Adverse effects: Common IV: local pain (may be severe), thrombophlebitis. Oral: usually only causes gastrointestinal adverse effects if significant serum concentrations occur, e.g. in renal impairment. Nausea, vomiting, diarrhoea and chills. Uncommon Nephrotoxicity including renal failure (see below). Rare Ototoxicity (discontinue if tinnitus occurs), interstitial nephritis, serious skin reactions (e.g. linear IgA bullous disease, exfoliative dermatitis, erythema multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis, vasculitis, drug rash with eosinophilia and systemic symptoms (DReSS)). Blood disorders including thrombocytopenia (may be immune-mediated), neutropenia (more likely after at least 1 week and total dose > 25 g), leukopenia, agranulocytosis, flushing of the upper body (“red man” syndrome (see below)), anaphylaxis, severe hypotension (with shock, cardiac arrest), superinfection, Clostridium difficile-associated disease. NePHROTOXICITy Although reports of frequency are conflicting, it is more common when used with aminoglycosides and in renal impairment. It appears to be related to vancomycin serum concentration. OTOTOXICITy Dizziness, vertigo and tinnitus can occur. Vancomycin alone rarely causes ototoxicity; risk is higher with prolonged use, in renal impairment and when given with other ototoxic drugs, e.g. aminoglycosides; deafness may be permanent. ReD MAN SyNDROMe Usually due to infusion being given too quickly. It is not an allergic reaction although symptoms are partly due to histamine release; they include fever, chills, erythema, facial and upper torso rash, which may be followed by hypotension, angioedema and itch. May be treated with antihistamines (e.g. promethazine); successful administration is usually possible by increasing the infusion time (e.g. to 120 minutes). Interactions with other medicines (* indicates severe): Amikacin: increased risk of nephrotoxicity and ototoxicity. Amphotericin B: possibly increased risk of nephrotoxicity. Capreomycin: increased risk of nephrotoxicity and ototoxicity. * Ciclosporin: increased risk of nephrotoxicity. * Furosemide: increased risk of ototoxicity. Gentamicin: increased risk of nephrotoxicity and ototoxicity. Halothane: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Ketamine: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Nitrous oxide: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Paromomycin: increased risk of otoxicity. Streptomycin: increased risk of nephrotoxicity and ototoxicity. * Suxamethonium: enhanced effects of suxamethonium. Thiopental: hypersensitivity-like reactions can occur with concomitant intravenous vancomycin. Notes: Injection may be given orally for Clostridium difficile infection (see Dose); flavouring syrups may be added to the solution at the time of administration. ADMINISTRATION Give over at least 60 minutes (rate not to exceed 10 mg/minute for doses > 500 mg) via central venous catheter if possible; avoid extravasation; never give IM. Do not mix with other drugs in parenteral solutions. WHO Model Formulary for Children 2010 117
    • 6 Anti-infective medicines References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 6.2.3 Antileprosy medicines Leprosy is a chronic mycobacterial infection due to Mycobacterium leprae, which is a slow-growing intracellular bacillus that infiltrates the skin, peripheral nerves, the nasal and other mucosa and the eyes; it affects people of all ages and both sexes. The incubation period between infection and appearance of leprosy is normally between 2 and 10 years, but may be up to 20 years. It is transmitted from person to person when bacilli are shed from the nose. For treatment purposes, patients may be classified as having either paucibacillary (PB) or multibacillary (MB) leprosy. The two forms may be distinguished by skin smears, but facilities are not always available to process them and their reliability is often doubtful. In practice, most leprosy programmes classify patients and choose a regimen based on the number of skin lesions, i.e. PB leprosy: one to five skin lesions; MB leprosy, more than five skin lesions. Rifampicin, clofazimine and dapsone are used in the treatment of leprosy and should always be used as combination therapy; this is essential to prevent the emergence of resistance. Lepra reactions are episodes of sudden increase in the activity of leprosy, and are often accompanied by neuritis. Reactions must always be treated promptly to prevent permanent nerve damage and disability. Leprosy multidrug therapy should continue without interruption during a lepra reaction. This reduces the frequency and severity of lepra reactions. Type 1 lepra reactions (reversal reactions) are delayed hypersensitivity reactions, characterized by redness and swelling of pre-existing skin lesions and possible increased motor/sensory loss before ulceration of the lesion. This may occur in either PB or MB leprosy. The type 2 lepra reaction (erythema nodosum leprosum [eNL]), characterized by fever and multiple red tender nodules, is an antibody response to dead leprosy bacteria and occurs only in MB leprosy. Clofazimine ATC code: J04BA01 Capsule: 50 mg; 100 mg Special Notes: Medicines used in the treatment of leprosy should never be used except in combination. Combination therapy is essential to prevent the emergence of drug resistance. Indications: Treatment of multibacillary (MB) leprosy (and where classification between MB and paucibacillary leprosy cannot be made) as part of combination therapy; treatment of type 2 lepra reactions (erythema nodosum leprosum). Precautions: Pre-existing gastrointestinal symptoms (reduce dose, increase dose interval or discontinue if symptoms develop during treatment); liver and renal impairment; may discolour soft contact lenses. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for about 24 hours. 118 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Dose: Multibacillary leprosy (in combination with dapsone and rifampicin). Oral: Child under 10 years 100 mg once a month and 50 mg twice a week. Continue treatment for 12 months; 10–12 years 150 mg once a month and 50 mg on alternate days. Continue treatment for 12 months. Type 2 lepra reaction (erythema nodosum leprosum). Oral: Child all ages 100 mg two or three times daily. Continue treatment for 3 months. 4–6 weeks treatment may be required before effect is seen. Adverse effects: Uncommon Reversible discoloration of skin, hair, cornea, conjunctiva, tears, sweat, sputum, faeces and urine, gastrointestinal pain, nausea, vomiting, diarrhoea, weight loss, gastrointestinal bleeding, severe mucosal and submucosal oedema, dry skin, acne-like eruptions, rashes, pruritus, photosensitivity, decreased sweat production, dry eyes. Rare Headache, drowsiness, dizziness, taste disorders, elevation of blood glucose concentration. Interactions with other medicines (* indicates severe): * Phenytoin: reduced phenytoin serum concentrations and loss of phenytoin efficacy. Notes: The drug is well tolerated and virtually non-toxic in the dosage used for multidrug therapy (MDT). The drug causes brownish black discoloration and dryness of skin. However, this disappears within a few months after stopping treatment. This should be explained to patients starting a MDT regimen for MB leprosy. References: estrada B. Leprosy. eMedicine. New york, WebMD, 2009 (http://emedicine.medscape.com/article/965605-overview, accessed 10 February 2010). WHO-recommended multi-drug therapy (MDT) regimens. Geneva, World Health Organization, 2010 (http://www.who.int/lep/ mdt/regimens/en/, accessed 10 February 2010). Dapsone ATC code: J04BA02 Tablet: 25 mg; 50 mg; 100 mg Special Notes: Medicines used in the treatment of leprosy should never be used except in combination. Combination therapy is essential to prevent the emergence of drug resistance. Indications: Treatment of leprosy as part of combination therapy (paucibacillary and multibacillary). Contraindications: Hypersensitivity to sulfones; severe anaemia. Precautions: Anaemia (treat severe anaemia before therapy, and monitor blood counts during treatment); susceptibility to haemolysis including G6PD deficiency (including breastfeeding affected infants); porphyria. BLOOD DISORDeRS On long-term treatment, patients and their carers should be told how to recognize blood disorders and advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, purpura, bruising or bleeding develop. SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. WHO Model Formulary for Children 2010 119
    • 6 Anti-infective medicines Dose: Paucibacillary leprosy (in combination with rifampicin). Oral: Child under 10 years 25 mg once daily. Continue treatment for 6 months; 10–12 years 50 mg once daily. Continue treatment for 6 months. Multibacillary leprosy (in combination with rifampicin and clofazimine). Oral: Child under 10 years 25 mg once daily. Continue treatment for 12 months; 10–12 years 50 mg once daily. Continue treatment for 12 months. Renal impairment: Increased levels can occur in renal impairment. Adverse effects: Common Gastrointestinal irritation, photosensitivity. Rare Haemolysis, methaemoglobinaemia, allergic dermatitis (rarely including toxic epidermal necrolysis and Stevens-Johnson syndrome), hepatitis, agranulocytosis, “dapsone syndrome” resembling mononucleosis (rare hypersensitivity reaction with symptoms including rash, fever, jaundice and eosinophilia), tachycardia, headache, nervousness, insomnia, blurred vision, paraesthesia, reversible peripheral neuropathy, psychoses. Interactions with other medicines (* indicates severe): Rifampicin: reduced plasma dapsone concentration. Sulfamethoxazole + trimethoprim: plasma concentration of both dapsone and trimethoprim may increase with concomitant use. Trimethoprim: plasma concentration of both dapsone and trimethoprim may increase with concomitant use. Notes: May cause photosensitivity. Patients with high acetylation rates or who are receiving treatment that affects acetylation may require a dosage adjustment. May be taken with food to reduce stomach upset. Tablets should be taken whole and small doses should be made up from 25 mg tablets. Do not split the tablet. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kemp CA, McDowell JM. Paediatric pharmacopoeia. 13th ed. Melbourne, Royal Children’s Hospital, 2002. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). MIMS Online. Sydney, UBM Medica, 2009 (http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010). Rifampicin ATC code: J04AB02 Solid oral dosage form: 150 mg; 300 mg Special Notes: Medicines used in the treatment of leprosy should never be used except in combination. Combination therapy is essential to prevent the emergence of drug resistance. Indications: Treatment of leprosy as part of combination therapy (paucibacillary and multibacillary). Contraindications: Hypersensitivity to rifamycins; jaundice. Precautions: Hepatic impairment; monitor liver function tests and blood counts in patients with liver disorders or on prolonged therapy; renal impairment (if dose above 600 mg daily); porphyria; discolours soft contact lenses. 120 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials IMPORTANT Advise patients on hormonal contraceptives to use additional means. NOTe Resumption of rifampicin treatment after a long interval may cause serious immunological reactions, resulting in renal impairment, haemolysis or thrombocytopenia; discontinue permanently if serious adverse effects occur. LIVeR DISORDeRS Patients or their carers should be told how to recognize signs of liver disorders and advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop. Dose: Paucibacillary leprosy (in combination with dapsone). Oral: Child under 10 years 300 mg once a month. Continue treatment for 6 months; 10–12 years 450 mg once a month. Continue treatment for 6 months. Multibacillary leprosy (in combination with dapsone and clofazimine). Oral: Child under 10 years 300 mg once a month. Continue treatment for 12 months; 10–12 years 450 mg once a month. Continue treatment for 12 months. PATIeNT ADVICe Take dose at least 30 minutes before a meal, since absorption is reduced by food. Hepatic impairment: Impaired elimination; monitor liver function; avoid or do not exceed 8 mg/kg daily. Adverse effects: Common Urine, tears, saliva and sputum coloured orange-red. Rare Alterations of liver function, jaundice, potentially fatal hepatitis (dose related; do not exceed maximum dose of 600 mg daily), anorexia, nausea, vomiting, diarrhoea, antibiotic-associated colitis, headache, drowsiness, rashes, fever, influenza-like syndrome, respiratory symptoms, collapse, shock, haemolytic anaemia, acute renal failure, thrombocytopenic purpura, oedema, muscular weakness, myopathy, exfoliative dermatitis, toxic epidermal necrolysis, pemphigoid reactions, leukopenia, eosinophilia, menstrual disturbances. Interactions with other medicines (* indicates severe): Abacavir: plasma concentration of abacavir possibly reduced. Amitriptyline: plasma concentration of amitriptyline possibly reduced. Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of rifampicin. Chloramphenicol: accelerated metabolism of chloramphenicol (reduced plasma chloramphenicol concentration). * Ciclosporin: accelerated metabolism of ciclosporin (reduced plasma ciclosporin concentration). * Contraceptives, oral: accelerated metabolism of estrogens and progestogens (reduced contraceptive effect). Dapsone: reduced plasma dapsone concentration. * Dexamethasone: accelerated metabolism of dexamethasone (reduced effect). Diazepam: metabolism of diazepam accelerated (reduced plasma concentration). Digoxin: plasma concentration of digoxin possibly reduced. Doxycycline: plasma doxycycline concentration possibly reduced. Efavirenz: reduced plasma concentration of efavirenz (increase efavirenz dose). * Fluconazole: accelerated metabolism of fluconazole (reduced plasma concentration). * Glibenclamide: possibly accelerated metabolism (reduced effect) of glibenclamide. * Haloperidol: accelerated metabolism of haloperidol (reduced plasma haloperidol concentration). * Hydrocortisone: accelerated metabolism of hydrocortisone (reduced effect). WHO Model Formulary for Children 2010 121
    • 6 Anti-infective medicines * Indinavir: metabolism accelerated by rifampicin (plasma indinavir concentration reduced; avoid concomitant use). * Levonorgestrel: accelerated metabolism of levonorgestrel (reduced contraceptive effect). Levothyroxine: accelerated metabolism of levothyroxine (may increase levothyroxine requirements in hypothyroidism). * Lopinavir: reduced plasma concentration of lopinavir (avoid concomitant use). * Medroxyprogesterone: accelerated metabolism of medroxyprogesterone (does not apply to injectable medroxyprogesterone acetate for contraception). * Nelfinavir: plasma concentration of nelfinavir significantly reduced (avoid concomitant use). * Nevirapine: reduced plasma concentration of nevirapine (avoid concomitant use). * Nifedipine: accelerated metabolism of nifedipine (plasma concentration significantly reduced). * Norethisterone: accelerated metabolism of norethisterone (reduced contraceptive effect). * Phenytoin: accelerated metabolism of phenytoin (reduced plasma concentration). * Prednisolone: accelerated metabolism of prednisolone (reduced effect). Propranolol: metabolism of propranolol accelerated (significantly reduced plasma concentration). * Quinidine: accelerated metabolism of quinidine (reduced plasma quinidine concentration). * Saquinavir: plasma concentration of saquinavir significantly reduced; avoid concomitant use. * Verapamil: accelerated metabolism of verapamil (plasma concentration significantly reduced). * Warfarin: accelerated metabolism of warfarin (reduced anticoagulant effect). Zidovudine: avoidance of rifampicin advised by manufacturer of zidovudine. Notes: Capsules should be swallowed whole. Avoid contact during dosing/preparation due to risk of contact sensitization. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. 6.2.4 Antituberculosis medicines Antituberculosis treatment in children The main objectives of antituberculosis treatment are to: 1. cure the patient of tuberculosis (TB) (by rapidly eliminating most of the bacilli) 2. prevent death from active TB or its late effects 3. prevent relapse of TB (by eliminating the dormant bacilli) 4. prevent the development of drug resistance (by using a combination of drugs) 5. decrease TB transmission to others. Children with TB usually have paucibacillary (low organism numbers) pulmonary disease. They also develop extrapulmonary TB more often than adults. Severe and disseminated TB (e.g. TB meningitis and miliary TB) occurs more frequently in young children (less than 3 years old). Both the bacillary load and the type of disease may influence the effectiveness of treatment regimens. Treatment outcomes in children are generally good, even in young and immunocompromised children, provided treatment is started promptly. Studies demonstrate that very few of the drug adverse events more commonly reported in adults occur as commonly in children, when used in doses suggested in WHO treatment regimens. 122 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Treatment regimens Anti-TB treatment is divided into two phases: an intensive phase and a continuation phase. The purpose of the intensive phase is to rapidly eliminate the majority of organisms and to prevent the emergence of drug resistance. This phase uses a greater number of drugs than the continuation phase. The purpose of the continuation phase is to eradicate the dormant organisms. Fewer drugs are generally used in this phase because the risk of acquiring drug resistance is low, as most of the organisms have already been eliminated. Daily treatment is preferred for therapy, but treatment can be given three times weekly provided the treatment is directly observed. Three times weekly therapy is not recommended in settings where there is high HIV-prevalence, or for HIV-positive individuals. Recommended dosages Note that dose recommendations for several first-line anti-TB medications have recently been revised. Recommended doses for several medications have been increased, because current evidence suggests that serum drug levels may be lower in children than in adults. Children with TB must be followed up regularly and have dosages adjusted for weight gained. Two or more new drugs should be added to any re-treatment regimen in cases of genuine failure of treatment. Children with TB who are co-infected with HIV HIV-infected children are at greater risk for TB infection and TB disease than children not infected with HIV. HIV-infected children also have a poorer response to TB treatment and higher rates of mortality associated with TB disease. The majority of deaths in HIV-infected children being treated for TB occur in the first 2 months of TB treatment during the intensive phase. Management of relapse and drug-resistant TB in children In childhood TB cases when anti-TB treatment fails or a relapse occurs, every effort should be made to find the most likely cause for the failure or relapse. Mycobacterial culture and drug susceptibility testing should be performed for all re-treatment cases. Drug-resistant TB is a public health problem in many countries. Second-line drugs are required to manage these infections. There is limited experience with the safety of many of these drugs in children. No drug is absolutely contraindicated in children; however, benefits have to be carefully weighed against risks. These drugs are indicated for the treatment of multidrug-resistant TB in children and should only be used in specialized centres. Ethambutol ATC code: J04AK02 Oral liquid: 25 mg/ml Tablet: 100 mg; 400 mg (hydrochloride) Indications: Treatment of tuberculosis, in combination with other drugs. Contraindications: Optic neuritis; severe renal impairment. Precautions: Visual disturbances; renal impairment. VISUAL DISTURBANCeS Patients should report visual disturbances immediately and discontinue treatment. WHO Model Formulary for Children 2010 123
    • 6 Anti-infective medicines Dose: Treatment of tuberculosis, in combination with other drugs. Oral: Infant or Child 20 mg/kg (range 15–25 mg/kg) once daily. NOTe Serum ethambutol concentrations should be monitored. The doses in this monograph are based on the 2009 WHO “Dosing instructions for the use of currently available fixed-dose combination TB medicines for children”. Therefore, they may differ from other paediatric TB treatment guidelines. Renal impairment: Mild/moderate: reduce dose; if creatinine clearance less than 30 ml/minute monitor plasma ethambutol concentration. Severe: avoid. Adverse effects: Uncommon Optic neuritis (reduced visual acuity and red/green colour blindness (early changes usually reversible, prompt withdrawal may prevent blindness)), gout, peripheral neuritis (especially in legs). Rare Rash, pruritus, urticaria, thrombocytopenia. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Dosing instructions for the use of currently available fixed-dose combination TB medicines for children. Geneva, World Health Organization, 2009 (http://www.stoptb.org/gdf/assets/documents/Interim Paediatric FDCs detailed dosing instructions_Sept09. pdf, accessed 10 February 2010). Ethambutol efficacy and toxicity: literature review and recommendations for daily and intermittent dosage in children. Geneva, World Health Organization, 2006 (http://www.who.int/tb/publications/2006/en/index.html, accessed 10 February 2010). Graham SM et al. ethambutol in tuberculosis: time to reconsider? Archives of Disease in Childhood, 1998, 79:274–278. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Trebucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. International Journal of Tuberculosis and Lung Disease, 1997(1):12–15. Isoniazid ATC code: J04AC01 Oral liquid: 10 mg/ml Tablet: 100 mg; 300 mg Tablet (scored): 50 mg Severe and sometimes fatal hepatitis may occur; usually occurs within the first 3 months of treatment. Patients or their carers must be advised to report any prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea or vomiting, immediately. Special Notes: Also referred to as INH. Indications: Treatment of tuberculosis, in combination with other drugs; prophylaxis of tuberculosis. Contraindications: Drug-induced hepatic disease. Precautions: Hepatic impairment; risk of peripheral neuritis (prophylactic pyridoxine recommended) in patients with malnutrition, chronic renal failure, diabetes mellitus or HIV infection; epilepsy; slow acetylator status; history of psychosis; porphyria; renal impairment. 124 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials LIVeR DISORDeRS Patients or their carers should be told how to recognize signs of liver disease and be advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop. Dose: Treatment of tuberculosis (in combination with other drugs), prophylaxis of tuberculosis. Oral: Infant or Child greater than 3 months 10 mg/kg (range 10–15 mg/kg) once daily (maximum 300 mg daily). The doses in this monograph are based on the 2009 WHO “Dosing instructions for the use of currently available fixed-dose combination TB medicines for children”. Therefore, they may differ from other paediatric TB treatment guidelines. Renal impairment: Severe: reduce dose to maximum 4 mg/kg daily or 200 mg daily; risk of peripheral neuropathy. Hepatic impairment: Use with caution; monitor liver function regularly and frequently in the first 2 months. Adverse effects: Uncommon Nausea, vomiting, diarrhoea, gastrointestinal pain, constipation, dry mouth. Rare Hepatotoxicity (withdraw treatment), peripheral neuropathy, blood disorders (including agranulocytosis, haemolytic anaemia, aplastic anaemia), optic neuritis, toxic psychoses, seizures, hypersensitivity reactions (including fever, rashes, joint pain, erythema multiforme and purpura), systemic lupus erythematosus-like syndrome, pellagra, hyper-reflexia, difficulty with micturition, hyperglycaemia, gynaecomastia. Interactions with other medicines (* indicates severe): Amitriptyline: increased plasma concentration of isoniazid. Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of isoniazid. * Carbamazepine: increased plasma carbamazepine concentration (also isoniazid hepatotoxicity possibly increased). Cycloserine: increased risk of CNS toxicity. Diazepam: metabolism of diazepam inhibited. * Ethosuximide: metabolism of ethosuximide inhibited (increased plasma ethosuximide concentration and risk of toxicity). Halothane: possible potentiation of isoniazid hepatotoxicity. Ketamine: possible potentiation of isoniazid hepatotoxicity. Nitrous oxide: possible potentiation of isoniazid hepatotoxicity. p-Aminosalicylic acid: increased plasma concentration of isoniazid. * Phenytoin: metabolism of phenytoin inhibited (enhanced effect). Thiopental: possible potentiation of isoniazid hepatotoxicity. Notes: PATIeNT ADVICe Isoniazid should be taken on an empty stomach; if taken with food to reduce gastrointestinal irritation, oral absorption and bioavailability may be impaired. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Donald PR. A literature review of the pharmacokinetics of rifampicin, isoniazid and pyrazinamide and a recommendation for the dosages to be used in children. Geneva, World Health Organization, Unpublished 2007. Donald PR. Hepatotoxicity of antituberculosis agents in children: a literature review. Geneva, World Health Organization, Unpublished 2009. WHO Model Formulary for Children 2010 125
    • 6 Anti-infective medicines Dosing instructions for the use of currently available fixed-dose combination TB medicines for children. Geneva, World Health Organization, 2009 (http://www.stoptb.org/gdf/assets/documents/Interim Paediatric FDCs detailed dosing instructions_Sept09. pdf, accessed 10 February 2010). Frydenberg AR, Graham SM. Toxicity of first-line drugs for treatment of tuberculosis in children: review. Tropical Medicine and International Health, 2009, 14(11):1329–1337. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Pyrazinamide ATC code: J04AK01 Oral liquid: 30 mg/ml Tablet: 400 mg Tablet (dispersible): 150 mg Tablet (scored): 150 mg Special Notes: Also referred to as PZA. Indications: Treatment of tuberculosis, in combination with other medicines. Contraindications: Severe hepatic impairment; porphyria. Precautions: Hepatic impairment; renal impairment; diabetes mellitus (monitor blood glucose, may change suddenly); gout; concurrent medications associated with liver injury (particulary rifampicin). LIVeR DISORDeRS Patients or their carers should be told how to recognize signs of liver disease and be advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop. Dose: Treatment of tuberculosis, in combination with other medicines. Oral: Infant or Child 35 mg/kg (range 30–40 mg/kg) once daily. Maximum 2 g daily. The doses in this monograph are based on the 2009 WHO “Dosing instructions for the use of currently available fixed-dose combination TB medicines for children”. Therefore, they may differ from other paediatric TB treatment guidelines. Renal impairment: Severe impairment: reduce dose. Hepatic impairment: Monitor hepatic function, idiosyncratic hepatotoxicity more common. Severe hepatic impairment: avoid use. Adverse effects: Common Nausea, vomiting. Uncommon Rash, photosensitivity. Rare Flushing, dysuria, arthralgia, gout, sideroblastic anaemia, hepatotoxicity (including fever, anorexia, hepatomegaly, splenomegaly, jaundice, liver failure). Interactions with other medicines (* indicates severe): * Ciclosporin: reduced ciclosporin serum concentrations and potentially reduced immunosuppressive efficacy. Rifampicin: risk of severe hepatic injury. Zidovudine: decreased serum concentration and efficacy of pyrazinamide. 126 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. Dosing instructions for the use of currently available fixed-dose combination TB medicines for children. Geneva, World Health Organization, 2009 (http://www.stoptb.org/gdf/assets/documents/Interim Paediatric FDCs detailed dosing instructions_Sept09. pdf, accessed 10 February 2010). Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Rifampicin ATC code: J04AB02 Oral liquid: 20 mg/ml Solid oral dosage form: 150 mg; 300 mg Special Notes: Also referred to as rifampin. Indications: Treatment of tuberculosis, in combination with other drugs. Contraindications: Hypersensitivity to rifamycins; jaundice. Precautions: Hepatic impairment; liver function tests and blood counts required in liver disorders and on prolonged therapy; porphyria; discolours soft contact lenses. IMPORTANT Advise patients on hormonal contraceptives to use additional means. NOTe Resumption of rifampicin treatment after a long interval may cause serious immunological reactions, resulting in renal impairment, haemolysis or thrombocytopenia; discontinue permanently if serious adverse effects occur. LIVeR DISORDeRS Patients or their carers should be told how to recognize signs of liver disease and be advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop. Dose: Treatment of tuberculosis, in combination with other drugs. Oral: Infant or Child 15 mg/kg (range 10–20 mg) once daily. Maximum 600 mg daily. The doses in this monograph are based on the 2009 WHO “Dosing instructions for the use of currently available fixed-dose combination TB medicines for children”. Therefore, they may differ from other paediatric TB treatment guidelines. Renal impairment: Dose reduction not necessary. Hepatic impairment: Impaired elimination; monitor liver function; avoid or do not exceed 8 mg/kg daily. Adverse effects: Common Urine, tears, saliva and sputum coloured orange-red. Rare Alterations of liver function, jaundice, potentially fatal hepatitis, anorexia, nausea, vomiting, diarrhoea, headache, drowsiness, rashes, fever, influenza-like syndrome, respiratory symptoms, collapse, shock, haemolytic anaemia, acute renal failure, thrombocytopenic purpura, oedema, muscular weakness, myopathy, exfoliative dermatitis, toxic epidermal necrolysis, pemphigoid reactions, leukopenia, eosinophilia, menstrual disturbances. WHO Model Formulary for Children 2010 127
    • 6 Anti-infective medicines Interactions with other medicines (* indicates severe): Abacavir: plasma concentration of abacavir possibly reduced. Amitriptyline: plasma concentration of amitriptyline possibly reduced. Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of rifampicin. Chloramphenicol: accelerated metabolism of chloramphenicol (reduced plasma chloramphenicol concentration). * Ciclosporin: accelerated metabolism of ciclosporin (reduced plasma ciclosporin concentration). * Contraceptives, oral: accelerated metabolism of estrogens and progestogens (reduced contraceptive effect). Dapsone: reduced plasma dapsone concentration. * Dexamethasone: accelerated metabolism of dexamethasone (reduced effect). Diazepam: metabolism of diazepam accelerated (reduced plasma concentration). Digoxin: plasma concentration of digoxin possibly reduced. Doxycycline: plasma doxycycline concentration possibly reduced. Efavirenz: reduced plasma concentration of efavirenz (increase efavirenz dose). * Fluconazole: accelerated metabolism of fluconazole (reduced plasma concentration). * Glibenclamide: possibly accelerated metabolism (reduced effect) of glibenclamide. * Haloperidol: accelerated metabolism of haloperidol (reduced plasma haloperidol concentration). * Hydrocortisone: accelerated metabolism of hydrocortisone (reduced effect). * Indinavir: metabolism accelerated by rifampicin (plasma indinavir concentration reduced; avoid concomitant use). * Levonorgestrel: accelerated metabolism of levonorgestrel (reduced contraceptive effect). Levothyroxine: accelerated metabolism of levothyroxine (may increase levothyroxine requirements in hypothyroidism). * Lopinavir: reduced plasma concentration of lopinavir (avoid concomitant use). * Medroxyprogesterone: accelerated metabolism of medroxyprogesterone (does not apply to injectable medroxyprogesterone acetate for contraception). * Nelfinavir: plasma concentration of nelfinavir significantly reduced (avoid concomitant use). * Nevirapine: reduced plasma concentration of nevirapine (avoid concomitant use). * Nifedipine: accelerated metabolism of nifedipine (plasma concentration significantly reduced). * Norethisterone: accelerated metabolism of norethisterone (reduced contraceptive effect). * Phenytoin: accelerated metabolism of phenytoin (reduced plasma concentration). * Prednisolone: accelerated metabolism of prednisolone (reduced effect). Propranolol: metabolism of propranolol accelerated (significantly reduced plasma concentration). * Quinidine: accelerated metabolism of quinidine (reduced plasma quinidine concentration). * Saquinavir: plasma concentration of saquinavir significantly reduced; avoid concomitant use. * Verapamil: accelerated metabolism of verapamil (plasma concentration significantly reduced). * Warfarin: accelerated metabolism of warfarin (reduced anticoagulant effect). Zidovudine: avoidance of rifampicin advised by manufacturer of zidovudine. Notes: PATIeNT ADVICe Take dose at least 30 minutes before a meal, as absorption is reduced when taken with food. Capsules should be swallowed whole. Avoid contact during dosing/preparation due to risk of contact sensitization. 128 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Dosing instructions for the use of currently available fixed-dose combination TB medicines for children. Geneva, World Health Organization, 2009 (http://www.stoptb.org/gdf/assets/documents/Interim Paediatric FDCs detailed dosing instructions_Sept09. pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Streptomycin ATC code: J01GA01 Powder for injection: 1 g (as sulfate) in vial Special Notes: Intramuscular injection of streptomycin is very painful. Indications: Treatment of tuberculosis, in combination with other drugs. Contraindications: Hearing disorders; myasthenia gravis; hypersensitivity to aminoglycoside antibiotics. Precautions: Children (painful injection, avoid use if possible); renal impairment; infants (monitor renal, auditory and vestibular function, and plasma streptomycin concentrations); neuromuscular disorders; vertigo; tinnitus; hearing loss. Dose: Treatment of tuberculosis, in combination with other drugs. Deep IM injection: Infant or Child 20–40 mg/kg once daily. Maximum 1 g daily. NOTe 1 hour (peak) concentration should be 15–40 mg/litre; pre-dose (trough) concentration should be less than 5 mg/litre (less than 1 mg/litre in renal impairment). Renal impairment: Mild to moderate: extend dosing frequency. Monitor plasma concentrations. Severe: avoid use. Adverse effects: Common Pain and abscess at injection site. Uncommon Vestibular and auditory damage, nephrotoxicity, hypersensitivity reactions (withdraw treatment), paraesthesia of mouth, nausea, vomiting, rash, hypomagnesaemia on prolonged therapy. Rare Antibiotic-associated colitis, haemolytic anaemia, aplastic anaemia, agranulocytosis, thrombocytopenia. Interactions with other medicines (* indicates severe): * Alcuronium: enhanced muscle relaxant effect. Amphotericin B: increased risk of nephrotoxicity. * Ciclosporin: increased risk of nephrotoxicity. * Cisplatin: increased risk of nephrotoxicity and possibly of ototoxicity. * Furosemide: increased risk of ototoxicity. * Neostigmine: antagonism of effect of neostigmine. * Pyridostigmine: antagonism of effect of pyridostigmine. WHO Model Formulary for Children 2010 129
    • 6 Anti-infective medicines * Suxamethonium: enhanced muscle relaxant effect. Vancomycin: increased risk of nephrotoxicity and ototoxicity. * Vecuronium: enhanced muscle relaxant effect. Notes: ReCONSTITUTION AND ADMINISTRATION Reconstitute following manufacturer’s instructions. For IM injection, inject deep intramuscularly into a large muscle mass. Administer at a concentration not to exceed 500 mg/mL. Rotate injection sites. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Amikacin ATC code: J01GB06 Powder for injection: 100 mg; 500 mg; 1 g in vial Special Notes: Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: Hypersensitivity to amikacin or aminoglycoside antibiotics. Precautions: Renal impairment; pre-existing vestibular or auditory impairment; concomitant anaesthesia or neuromuscular blockers; conditions characterized by muscle weakness; myasthenia gravis; concomitant neurotoxic, ototoxic or nephrotoxic drugs; neonates and infants; dehydration. Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. IV or IM: Infant or Child 15–30 mg/kg once daily (maximum 1 g). NOTe Pre-dose (trough) concentration should be less than 5 mg/litre for once daily dosing. Renal impairment: Dosage adjustment is required in patients with renal impairment. Patients should receive the usual loading dose; however, subsequent doses and/or dosing intervals should be adjusted. Adjustment may be based on amikacin serum levels. Target amikacin serum levels for once daily dosing: pre-dose (trough) concentration should be < 5 mg/litre. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Ototoxicity, nephrotoxicity. Uncommon Rash, purpura, urticaria and alopecia. Rare exfoliative dermatitis, myasthenia gravis. Interactions with other medicines (* indicates severe): * Alcuronium: enhanced effects of alcuronium. Amphotericin B: increased risk of nephrotoxicity. 130 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials * Benzylpenicillin: concomitant penicillin and aminoglycoside therapy has been reported to result in inactivation of the aminoglycoside. Preferable to separate administration by 1 hour. * Ciclosporin: increased risk of nephrotoxicity. * Cisplatin: increased risk of nephrotoxicity and possibly of ototoxicity. * Furosemide: increased risk of ototoxicity. * Neostigmine: antagonism of effects of neostigmine. * Pyridostigmine: antagonism of effects of pyridostigmine. * Suxamethonium: enhanced effects of suxamethonium. Vancomycin: increased risk of nephrotoxicity and ototoxicity. * Vecuronium: enhanced effects of vecuronium. Notes: ADMINISTRATION Administer by intramuscular injection or slow intermittent intravenous infusion over 30 minutes at a final concentration not to exceed 10 mg/ml. For intravenous infusion, dilute with glucose 5% or sodium chloride 0.9% or compound sodium lactate. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Capreomycin ATC code: J04AB30 Powder for injection: 1 g in vial The use of capreomycin in patients with renal insufficiency or pre-existing auditory impairment must be undertaken with great caution. Risk of additional cranial nerve VIII impairment or renal injury. Since other parenteral antituberculosis agents (streptomycin, viomycin) also have similar and sometimes irreversible toxic effects, particularly on cranial nerve VIII and renal function, simultaneous administration of these agents with capreomycin is not recommended. Use with non-antituberculosis drugs (polymyxin A sulfate, colistin sulfate, amikacin, gentamicin, tobramycin, vancomycin, kanamycin and neomycin) having ototoxic or nephrotoxic potential, should be undertaken only with great caution. Special Notes: Monitor body weight monthly and adjust dose accordingly. Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: Hypersensitivity to aminoglycoside antibiotics. Precautions: Auditory impairment; concomitant use with streptomycin or viomycin; renal impairment; renal injury; myasthenia gravis. WHO Model Formulary for Children 2010 131
    • 6 Anti-infective medicines Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. IV or IM: Child 15–30 mg/kg (maximum 1 g) once daily. Renal impairment: Use with caution. In all degrees of impairment, dosing frequency should be reduced to 2–3 times weekly. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Injection site pain, eosinophilia, leukopenia, electrolyte disturbances (including hypokalaemia, hypocalcaemia, hypomagnesaemia, hyponatraemia and hypochloraemia), ototoxicity. Uncommon Urticaria and rash, changes in liver function tests, neuromuscular blockade. Rare Thrombocytopenia, nephrotoxicity. Interactions with other medicines (* indicates severe): * Alcuronium: enhanced or prolonged neuromuscular blockade. Amikacin: amikacin toxicity (ototoxicity, nephrotoxicity). * Atracurium: enhanced or prolonged neuromuscular blockade. * Cisatracurium: enhanced or prolonged neuromuscular blockade. * Doxacurium: enhanced or prolonged neuromuscular blockade. * Fazadinium: enhanced or prolonged neuromuscular blockade. * Gallamine: enhanced or prolonged neuromuscular blockade. Gentamicin: gentamicin toxicity (ototoxicity, nephrotoxicity). * Hexafluorenium: enhanced or prolonged neuromuscular blockade. Kanamycin: kanamycin toxicity (ototoxicity, nephrotoxicity). * Metocurine: enhanced or prolonged neuromuscular blockade. * Mivacurium: enhanced or prolonged neuromuscular blockade. Netilmicin: netilmicin toxicity (ototoxicity, nephrotoxicity). * Pancuronium: enhanced or prolonged neuromuscular blockade. * Pipecuronium: enhanced or prolonged neuromuscular blockade. * Rapacuronium: enhanced or prolonged neuromuscular blockade. * Rocuronium: enhanced or prolonged neuromuscular blockade. Streptomycin: streptomycin toxicity (ototoxicity, nephrotoxicity). * Suxamethonium: enhanced or prolonged neuromuscular blockade. Tobramycin: tobramycin toxicity (ototoxicity, nephrotoxicity). * Tubocurarine: enhanced or prolonged neuromuscular blockade. * Vecuronium: enhanced or prolonged neuromuscular blockade. Notes: ADMINISTRATION Reconstitute with 0.9% sodium chloride or water for injection. Administer by deep intramuscular injection into a large muscle or dilute further with 0.9% sodium chloride and infuse over 60 minutes. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Capastat Product Information. Aspen, 2010 (http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=16185, accessed 10 February 2010). 132 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Cycloserine ATC code: J04AB01 Solid oral dosage form: 250 mg Special Notes: Safety and effectiveness in paediatrics have not been established. Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: epilepsy; depression; severe anxiety; psychosis; porphyria; severe renal impairment. Precautions: Neuropsychiatric status assessed at least monthly, more frequently if symptoms develop; renal impairment. Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Oral: Child 5–10 mg/kg twice daily (initially 5 mg/kg/dose and adjust according to blood concentration and response). Maximum 1 g daily. NOTe Serum concentration measurements aiming for a peak concentration of 20–35 mg/ml are often useful in determining the optimum dose for a given patient. Measure 3–4 hours after dose. Renal impairment: Avoid use in all degrees of renal impairment. Adverse effects: Common Neurological (headache, dizziness, vertigo, drowsiness, tremor, seizures, confusion, psychosis, depression). Uncommon Rash. Rare Megaloblastic anaemia, changes in liver function tests, heart failure. Interactions with other medicines (* indicates severe): * Alcohol: increased risk of seizures. Isoniazid: increased risk of CNS toxicity. Notes: Penetrates the cerebrospinal fluid. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). WHO Model Formulary for Children 2010 133
    • 6 Anti-infective medicines Ethionamide ATC code: J04AD03 Tablet: 125 mg; 250 mg Special Notes: Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis and tuberculosis meningitis. Contraindications: Severe hepatic impairment. Precautions: AIDS infection (drug malabsorption may be a problem); diabetes mellitus; renal impairment; hepatic impairment. Dose: Treatment of multidrug-resistant tuberculosis and tuberculosis meningitis. Oral: Child 15–20 mg/kg once daily if tolerated; divided doses if necessary. Maximum 1 g/day. Renal impairment: Severe: reduce to 50% of dose. Hepatic impairment: Mild and moderate impairment: use with caution. Severe impairment: avoid use. Adverse effects: Common Gastrointestinal disturbance (see below). Uncommon Hepatotoxicity. Rare Hypotension, rash, fever, hypoglycaemia, hypothyroidism, gynaecomastia, photosensitivity, thrombocytopenia, encephalopathy, neuropathy, seizures, visual disturbances, ototoxicity. GASTROINTeSTINAL ADVeRSe eFFeCTS Gastrointestinal irritation is the major limiting factor in the therapeutic use of ethionamide. The most frequent adverse effects of ethionamide are nausea, vomiting and diarrhoea. Anorexia, excessive salivation, stomatitis and a metallic taste in the mouth occur less frequently. Abdominal discomfort, described as epigastric pain or burning, is common with therapeutic doses. These effects appear to be dose related. In general, half of the patient population is unable to tolerate 1 g of ethionamide as a single dose. Gastrointestinal effects are more common in females than males, and are less common in children. Persons of Asian or African descent reportedly tolerate this drug better than those of european descent. Interactions with other medicines (* indicates severe): Aminosalicylic acid: excessive adverse effects (GI distress and hepatotoxicity). Cycloserine: neurological adverse effects, including seizures. Ethambutol: excessive adverse effect (GI distress, headache, confusion, neuritis and hepatotoxicity). Isoniazid: increased isoniazid levels, peripheral neuritis, hepatotoxicity and encephalopathy. Pyrazinamide: hepatotoxicity. Rifampicin: hepatotoxicity. Notes: Concurrent administration of pyridoxine may reduce peripheral neuropathy. Administration of an antiemetic agent 30 minutes prior to ethionamide and administration of ethionamide at bedtime have been suggested in patients experiencing gastrointestinal adverse effects. Baseline liver function tests including serum transaminases, bilirubin and alkaline phosphatase should be obtained and regularly monitored (e.g. every 2–4 weeks) during ethionamide therapy. 134 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Kanamycin ATC code: J01GB04 Powder for injection: 1 g vial Special Notes: Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: Intestinal obstruction. Precautions: Concomitant administration with nephrotoxic or ototoxic antibiotics; concomitant administration with rapid acting diuretic agents; cross-allergenicity among other aminoglycosides (see Notes); infant botulism; myasthenia gravis; impaired neuromuscular transmission; parkinsonism; renal impairment; hepatic impairment; vestibular impairment. Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. IM or IV: Neonate with birth weight of less than 2 kg and aged 7 days or less 7.5 mg/kg every 12 hours; birth weight of more than 2 kg and aged 7 days or less 10 mg/kg every 12 hours; birth weight of 2 kg or less and aged greater than 7 days 10 mg/kg every 12 hours; birth weight of more than 2 kg and aged greater than 7 days 10 mg/kg every 8 hours. Infant or Child 15–30 mg/kg once daily (maximum 1 g daily). NOTe Whenever possible, dosage should be guided by kanamycin serum concentrations. Maintain optimal peak serum levels of 15–30 micrograms/ml. Suitable times to collect blood for kanamycin assays are 1 hour after an IM dose or 30 minutes after an IV dose (peak) then just prior to the next dose (trough). Renal impairment: The dosage of kanamycin must be reduced in patients with impaired renal function. Mild impairment: 60–90% of the normal dose every 8–12 hours. Moderate impairment: 30–70% of the dose every 12 hours. Severe impairment: 20–30% of the dose every 24–48 hours. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nephrotoxicity, ototoxicity, local irritation or pain after IM injection. Uncommon Neuromuscular blockade. Rare Skin rash, drug fever, headache, paraesthesia, nausea, vomiting and diarrhoea. Interactions with other medicines (* indicates severe): * Penicillins: loss of kanamycin activity. * Neuromuscular blocking drugs: enhanced and/or prolonged neuromuscular blockade which may lead to respiratory depression and paralysis. WHO Model Formulary for Children 2010 135
    • 6 Anti-infective medicines Loop diuretics: an increased risk of ototoxicity (tinnitus, transient or permanent hearing loss, dizziness, vertigo). Carboplatin: increased ototoxicity. Cidofovir: nephrotoxicity. Ciclosporin: renal dysfunction or nephrotoxicity. Tacrolimus: additive or synergistic renal function impairment. Typhoid vaccine, live: decreased immunological response to the typhoid vaccine. Notes: 62.2% of patients allergic to kanamycin demonstrated cross-sensitivity to gentamicin. Amikacin and kanamycin are very similar and have almost 100% cross-resistance. Occasionally, some vials may darken during the shelf-life of the product, but this does not indicate a loss of potency. ADMINISTRATION INSTRUCTIONS The minimum dilution of kanamycin is 2.5–5 mg/ml administered over 30–60 minutes. Direct intravenous push is not recommended. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Kantrex Product Information. Bristol-Myers Squibb, 2008 (http://www.rxlist.com/kantrex-drug.htm, accessed 10 February 2010). Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). Ofloxacin ATC code: J01MA01 Tablet: 200 mg; 400 mg Special Notes: Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Levofloxacin may be an alternative based on availability and programme considerations. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: Pregnancy; breastfeeding. Precautions: Tendinitis and tendon rupture; central nervous system disorders (may predispose patient to seizures or lower seizure threshold); co-administration with class IA (e.g. procainamide, quinidine) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents should be avoided; diabetic patients, especially patients receiving oral hypoglycemic agents or insulin (may cause hyperglycaemia or hypoglycaemia); excessive sunlight (risk for phototoxic reactions); hepatic impairment; renal impairment. Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Oral: Child 7.5–10 mg/kg twice daily. Maximum 800 mg/day. Renal impairment: All degrees of renal impairment: increased risk of seizure; dosage adjustment recommended; seek specialist advice. Hepatic impairment: elimination may be reduced; reduce dose in severe liver disease. 136 WHO Model Formulary for Children 2010
    • 6.2 Antibacterials Adverse effects: Common Rash, photosensitivity, nausea, vomiting, arthropathy, arthritis, diarrhoea, taste disturbance, insomnia, headache, dizziness. Uncommon Seizures, hypoglycaemia or hyperglycaemia. Rare Arrhythmias including QT prolongation, hepatic impairment/failure, blood dyscrasias, myopathy, arthralgia, tendon rupture, nephrotoxicity. Interactions with other medicines (* indicates severe): Antacids (aluminium hydroxide; magnesium hydroxide): reduced absorption of ofloxacin. * Amiodarone: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). * Artemether + lumefantrine: manufacturer of artemether with lumefantrine advises avoid concomitant use. * Ciclosporin: increased risk of nephrotoxicity. Contraceptives, oral: contraceptive effect of estrogens possibly reduced (risk probably small). Ferrous salts: absorption of ofloxacin reduced by oral ferrous salts. * Flecainide: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). * Ibuprofen: possible increased risk of convulsions. * Quinidine: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). * Sotalol: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest). Theophylline: an increased risk of elevated theophylline concentrations. Typhoid vaccine, live: a decreased immunological response to the typhoid vaccine. * Warfarin: enhanced anticoagulant effect. Zinc sulfate: reduced absorption of ofloxacin. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2006 (http:// whqlibdoc.who.int/publications/2006/9241546956_eng.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). p-Aminosalicylic acid ATC code: J04AA01 Granules: 4 g in sachet Tablet: 500 mg Special Notes: Also referred to as PAS and as 4-aminosalicylic acid (4-ASA). Second-line medicines should be reserved for the treatment of multidrug-resistant tuberculosis (MDR-TB) and should be used in specialized centres adhering to WHO standards for TB control. Indications: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Contraindications: Hypersensitivity to aminosalicylic acid products; end-stage renal disease. WHO Model Formulary for Children 2010 137
    • 6 Anti-infective medicines Precautions: Glucose-6-phosphate dehydrogenase (G6PD) deficiency (risk of haemolysis); hepatic impairment; peptic ulcer disease; renal impairment; congestive heart failure; patients on therapy of more than 1 month should be considered for maintenance vitamin B12. Dose: Treatment of multidrug-resistant tuberculosis, in combination with other drugs. Oral: Child 200–300 mg/kg per day in 2–4 divided doses. Maximum 10 g daily. Renal impairment: Not recommended to be used in patients with severe renal impairment. Hepatic impairment: Use with caution. Increase laboratory and clinical monitoring. Dose reduction not considered necessary. Adverse effects: Common Nausea, vomiting, diarrhoea, abdominal pain. Rare Hepatotoxicity, haemolysis, fever, rash, blood dyscrasias, hypoglycaemia, crystalluria, encephalopathy. Interactions with other medicines (* indicates severe): * Digoxin: reduced digoxin serum concentrations. Ethionamide: excessive adverse effects (GI distress and hepatotoxicity). Isoniazid: reduction in the acetylation of isoniazid (increased isoniazid levels). Vitamin B12: reduced absorption of vitamin B12. Notes: PATIeNT ADVICe Should be taken with acidic food or drink (yoghurt, apple sauce or fruit juice). Granules should be stored in the refrigerator. Can be stored at room temperature for short periods of time. Do not use granules if packet is swollen or the granules have lost their tan colour and have turned dark brown or purple. Sprinkle granules on apple sauce or yogurt or suspend in tomato, orange, grapefruit, grape, cranberry, apple or fruit juice containing drinks. Patients should be advised that the skeleton of the granules may be seen in the stool. References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paser Product Information. Jacobus, 2004 (http://www.rxlist.com/paser-drug.html, accessed 10 February 2010). Treatment of tuberculosis guidelines. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf, accessed 10 February 2010). Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003 (http://www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm, accessed 10 February 2010). 6.3 Antifungal medicines Fungal infections are increasing in prevalence globally, and can be classified as superficial or systemic. Superficial infections affect the skin, hair, nails or mucous membranes; systemic fungal infections affect the body as a whole. Systemic fungal infections may occur as opportunistic infections in patients who are immunocompromised, and are associated with high mortality rates. Duration of therapy depends on the initial severity of the infection and the clinical response of the patient. In some infections, a satisfactory response is only obtained after several months or more of continuous treatment. 138 WHO Model Formulary for Children 2010
    • 6.3 Antifungal medicines Fluconazole ATC code: J02AC01 Capsule: 50 mg Injection: 2 mg/ml in vial Oral liquid: 10 mg/ml Rare cases of fluconazole-associated hepatotoxicity, including fatalities, have been reported. Indications: Systemic mycoses including histoplasmosis, non-meningeal coccidioidomycosis, paracoccidioidomycosis and blastomycosis; treatment and, in HIV and other immunosuppressed patients, prophylaxis of cryptococcal meningitis; prevention of fungal infections in immunocompromised patients; oesophageal and oropharyngeal candidiasis, vaginal candidiasis and systemic candidiasis. Contraindications: Acute porphyria. Precautions: Renal impairment; monitor liver function: discontinue if signs or symptoms of hepatic disease (risk of hepatic necrosis); concomitant hepatotoxic drugs; susceptibility to QT interval prolongation; patients with proarrhythmic conditions. Dose: Systemic mycoses. Oral or IV: Child over 2 years 3–6 mg/kg (maximum 200 mg) daily for at least 6 months. Cryptococcal meningitis following amphotericin B induction therapy or systemic candidiasis (in patients unable to tolerate amphotericin B). Oral or IV: Neonate under 2 weeks 6–12 mg/kg every 72 hours; 2–4 weeks 6–12 mg/kg every 48 hours. Infant or Child 6–12 mg/kg (maximum 800 mg) daily. Treatment should continue according to response and should be for at least 8 weeks for cryptococcal meningitis. Prevention of relapse of cryptococcal meningitis in AIDS patients after completion of primary therapy. Oral or IV: Infant or Child 6 mg/kg (maximum 200 mg) daily. Mucosal candidiasis (except genital). Oral or IV: Neonate under 2 weeks 3–6 mg/kg on first day then 3 mg/kg every 72 hours; 2–4 weeks 3–6 mg/kg on first day then 3 mg/kg every 48 hours. Infant or Child 3–6 mg/kg on the first day, then 3 mg/kg daily (maximum 100 mg) for 7–14 days. Treat for 14–30 days for other mucosal infections such as oesophagitis, candiduria and non- invasive bronchopulmonary infections. Vaginal candidiasis. Oral: Child post-puberty 150 mg as a single dose. WHO Model Formulary for Children 2010 139
    • 6 Anti-infective medicines Prevention of fungal infections in immunocompromised patients. Oral or IV: Neonate under 2 weeks 3–12 mg/kg every 72 hours according to duration and extent of neutropenia; 2–4 weeks 3–12 mg/kg every 48 hours according to duration and extent of neutropenia. Infant or Child 3–12 mg/kg (maximum 400 mg) daily according to duration and extent of neutropenia. Commence treatment before anticipated onset of neutropenia and continue for 7 days after neutrophil count in desirable range. Renal impairment: Reduce dose in mild to severe impairment by 50%. Hepatic impairment: Use with caution. Adverse effects: Common Rash, headache, nausea, vomiting, abdominal pain, diarrhoea, elevated liver enzymes. Uncommon Anorexia, fatigue, dizziness, constipation. Rare Oliguria, hypokalaemia, seizures, paraesthesia, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis (severe skin reactions more common in patients with AIDS), prolonged QT interval, torsades de pointes, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including hepatic failure, angioedema, anaphylactic/anaphylactoid reactions. Interactions with other medicines (* indicates severe): Fluconazole can cause prolonged QT interval and torsades de pointes; avoid concomitant use of other cardiotoxic or arrhythmogenic drugs. Amphotericin B: possible antagonism of effect of amphotericin. * Artemether + lumefantrine: manufacturer of artemether with lumefantrine advises to avoid concomitant use. Carbamazepine: fluconazole may inhibit metabolism of carbamazepine and may increase concentration and risk of adverse effects; monitor carbamazepine concentration and for adverse effects. * Ciclosporin: metabolism of ciclosporin inhibited (increased plasma concentration). Contraceptives, oral: anecdotal reports of failure of estrogen containing contraceptives. Diazepam: fluconazole may inhibit diazepam’s metabolism, increasing the risk of adverse effects. Ibuprofen: fluconazole may inhibit ibuprofen’s metabolism, increasing its concentration and may increase risk of adverse effects. * Nevirapine: increased plasma concentration of nevirapine. * Phenytoin: plasma concentration of phenytoin increased (consider reducing dose of phenytoin). * Rifampicin: accelerated metabolism of fluconazole (reduced plasma concentration). Ritonavir: plasma concentration of fluconazole increased by ritonavir. Saquinavir: plasma concentration of saquinavir possibly increased. * Warfarin: enhanced anticoagulant effect. * Zidovudine: increased plasma concentration of zidovudine (increased risk of toxicity). Notes: For intravenous infusion, give over 60 minutes at a maximum rate of 200 mg/hour. Higher doses are best infused over 2 hours. Food decreases the rate but not the extent of absorption. Bioavailability is excellent at > 90%. Fluconazole oral liquid may contain sodium benzoate and should be used with caution in neonates. 140 WHO Model Formulary for Children 2010
    • 6.3 Antifungal medicines References: Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Griseofulvin ATC code: D01BA01 Oral liquid: 25 mg/ml Solid oral dosage form: 125 mg; 250 mg Special Notes: The formulations and doses in this formulary refer to microsize (fine particle) griseofulvin and these are not equivalent to ultramicrosize (ultra microfine crystal) formulations. Indications: Fungal infections of the skin, scalp or hair where topical treatment has failed or is inappropriate. Contraindications: Severe liver disease; pregnancy (avoid pregnancy and use additional non- hormonal contraception during and for 1 month after treatment; men should not father children within 6 months of treatment); porphyria; systemic lupus erythematosus (risk of exacerbation). Precautions: Avoid exposure to intense sunlight to prevent photosensitivity reactions; penicillin hypersensitivity (cross-reactivity with griseofulvin is possible); pre-existing hepatic insufficiency (closely monitor hepatic function throughout treatment); blood disorders (monitor blood count weekly during first month of treatment). SKILLeD TASKS Warn patient or carer about the risk of undertaking tasks requiring attention or coordination, for example riding a bike or operating machinery, for 24 hours. Dose: Fungal infections of the skin, scalp or hair where topical treatment has failed or is inappropriate. Oral: Infant or Child 10–20 mg/kg (maximum 1 g) once daily or in divided doses. Up to 25 mg/kg/day for 6–8 weeks may be required for the treatment of tinea capitis. Duration of treatment depends on the infection and thickness of keratin at site of infection. As a guide: at least 4 weeks for skin and hair, at least 6 weeks for scalp ringworm and in severe hair, skin and scalp infections, up to 3 months. Renal impairment: Dose reduction not necessary. Hepatic impairment: Contraindicated in severe liver disease. Adverse effects: Common Headache, nausea, diarrhoea, anorexia. Uncommon Photosensitivity, urticaria, rash, blurred vision, confusion, fatigue, dizziness, taste disturbance. Rare Precipitation/exacerbation of systemic lupus erythematosus, vomiting, severe diarrhoea, menstrual irregularities, leukopenia, hepatotoxicity, hypersensitivity, e.g. serum sickness-like reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis. Interactions with other medicines (* indicates severe): Ciclosporin: plasma ciclosporin concentration possibly reduced. WHO Model Formulary for Children 2010 141
    • 6 Anti-infective medicines * Contraceptives, oral: accelerated metabolism of estrogens and progestogens (reduced contraceptive effect). * Ethanol: disulfiram-like reaction (nausea, vomiting, diarrhoea, flushing, tachycardia, hypotension). * Levonorgestrel: accelerated metabolism of levonorgestrel (reduced contraceptive effect). * Medroxyprogesterone: accelerated metabolism of medroxyprogesterone (does not apply to injectable medroxyprogesterone acetate for contraception). * Norethisterone: accelerated metabolism of norethisterone (reduced contraceptive effect). Phenobarbital: reduction in absorption of griseofulvin (reduced effect). * Warfarin: reduced anticoagulant effect. Notes: Fatty meals will increase griseofulvin absorption. Administer with a fatty meal or with food or milk to improve absorption and to avoid gastrointestinal upset. PATIeNT ADVICe Avoid consumption of alcoholic beverages during treatment with griseofulvin. Avoid sun exposure, wear protective clothing and use sunscreen as griseofulvin may make you more sensitive to sunlight. The contraceptive pill will not be as effective while you are taking griseofulvin; you should use additional contraception, e.g. condoms, during treatment and for 4 weeks afterwards. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Nystatin ATC code: A07AA02 Lozenge: 100 000 IU Oral liquid: 10 mg/ml; 100 000 IU/ml Tablet: 100 000 IU; 500 000 IU Special Notes: Nystatin should not be used for the treatment of systemic mycoses. Indications: Oral, oesophageal and intestinal candidiasis. Dose: Treatment of oral candidiasis. Oral: Child all ages 100 000 units four times daily after feeds. Treatment is usually given for 7 days and continued for 2 days after lesions have healed. Treatment of intestinal and oesophageal candidiasis. Oral: Child all ages 100 000 units four times daily after feeds. Immunocompromised children may require 500 000 units four times daily. Renal impairment: Dose reduction not necessary. Hepatic impairment: Dose reduction not necessary. 142 WHO Model Formulary for Children 2010
    • 6.3 Antifungal medicines Adverse effects: Common Nausea, vomiting, diarrhoea (more severe with doses > 5 million units daily). Rare Oral irritation and sensitization, rash and erythema multiforme (Stevens-Johnson syndrome). Interactions with other medicines (* indicates severe): There are no known interactions where it is recommended to avoid concomitant use. Notes: each mg of nystatin contains not less than 4400 units of activity. PATIeNT ADVICe Oral liquid: shake well before use. It is best to use the oral liquid after (rather than before) a meal or drink. Should be swished around mouth and retained for as long as possible then swallowed. Continue to use for 2 days after your symptoms/lesions disappear. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Amphotericin B ATC code: J02AA01 Powder for injection: 50 mg in vial As deoxycholate or liposomal Amphotericin B is available as deoxycholate, lipid complex and liposomal; these should not be considered interchangeable. Care with product formulation. Large overdoses have occurred when conventional formulations were dispensed inadvertently for lipid based or liposomal products. Single daily doses of conventional amphotericin B formulation never exceed 1.5 mg/kg. Anaphylaxis has been reported with amphotericin B containing drugs; facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. Intravenous amphotericin B is used primarily for the treatment of patients with progressive fungal infections; not to be used for non-invasive forms of fungal disease. Special Notes: Also known as amphotericin. Amphotericin B is available as the conventional deoxycholate complex and liposomal forms. It is also available in a lipid complex form (not included in the 2nd WHO Model list of essential medicines for children). Indications: Life-threatening fungal infections including histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis, aspergillosis, cryptococcosis, mucormycosis, sporotrichosis and candidiasis. Contraindications: Known hypersensitivity. Precautions: Close medical supervision throughout treatment and initial test dose required (see Anaphylaxis, below); renal impairment; hepatic and renal function tests; blood counts and plasma electrolyte (including potassium and magnesium concentration) monitoring; avoid rapid infusion (risk of arrhythmias). WHO Model Formulary for Children 2010 143
    • 6 Anti-infective medicines LIPOSOMAL Diabetes as each 50 mg vial of liposomal amphotericin B contains 900 mg of sucrose. ANAPHyLAXIS Anaphylaxis occurs rarely with intravenous amphotericin B and a test dose is advisable before the first infusion. The patient should be observed for at least 30 minutes after the test dose. Prophylactic antipyretics or hydrocortisone should only be used in patients who have previously experienced acute adverse reactions (in whom continued treatment with amphotericin B is essential). Dose: Conventional amphotericin B (as deoxycholate) Systemic fungal infections. IV: Neonate, Infant or Child initial test dose of 100 micrograms/kg (maximum 1 mg) included as part of first dose, then 250 micrograms/kg daily, gradually increased up to 1 mg/kg daily or in severe infection, up to maximum of 1.5 mg/kg daily. Prolonged treatment is usually necessary. For prolonged treatment, a higher dose (maximum 1.5 mg/kg) may be given on alternate days. If treatment is interrupted for longer than 7 days, recommence at 250 micrograms/kg daily and increase gradually. Liposomal amphotericin B Systemic fungal infections. IV: Neonate, Infant or Child initial test dose 100 micrograms/kg (maximum 1 mg) then 1 mg/kg once daily, increased in steps of 1 mg/kg daily up to 3 mg/kg once daily; maximum 5 mg/kg once daily if necessary for severe infection. Renal impairment: Mild to severe: use only if no alternative. No dosage reduction is necessary, but further impairment is likely with conventional (as deoxycholate) amphotericin B. Nephrotoxicity may be reduced with use of liposomal formulations. Hepatic impairment: Dose reduction not necessary. Adverse effects: Adverse effects are similar for all amphotericin B formulations; the rates depend on the formulation used; liposomal formulations are generally better tolerated. Common Fever, headache, nausea and vomiting, anorexia, hypokalaemia, hypomagnesaemia, diarrhoea, epigastric pain, muscle and joint pain, infusion reactions (see below), thrombophlebitis, anaemia, nephrotoxicity (see below). Uncommon Hypotension, hypertension, cardiac arrest, arrhythmias (rapid infusion of conventional amphotericin B), blood dyscrasias, gastrointestinal bleeding, elevated liver enzymes, hepatotoxicity, rash, neurological effects (e.g. seizures, confusion, blurred vision, hearing loss, tinnitus). Rare Anaphylactoid reactions, hyperkalaemia (especially in renal impairment), cardiovascular toxicity (including arrhythmias, eCG changes). NePHROTOXICITy Conventional (as deoxycholate) amphotericin B affects renal function in all patients; changes are dose related and generally reversible (except with cumulative doses > 3–5 g). Distal tubular damage may lead to loss of concentrating ability, renal tubular acidosis, nephrocalcinosis, hypokalaemia and hypomagnesaemia. Anuria or oliguria may occur. Risk is greater in those with renal impairment or when used with other nephrotoxic drugs. Nephrotoxicity may be associated with sodium depletion. Liposomal amphotericin B is less nephrotoxic than conventional (deoxycholate) amphotericin B. INFUSION ReACTIONS Include fever, chills, hypotension, anorexia, nausea, vomiting, headache, malaise, muscle and joint pain; usually lessen with continued treatment. Continuous infusion of conventional (as deoxycholate) amphotericin B reduces infusion reactions. With liposomal amphotericin B one or more acute infusion reactions (chest pain, hypoxia, dyspnoea, severe abdominal, flank or leg pain, flushing and urticaria) may occur; these may be related to the liposomal component; frequency is very variable. 144 WHO Model Formulary for Children 2010
    • 6.3 Antifungal medicines Interactions with other medicines (* indicates severe): Amphotericin B is nephrotoxic; administration with other nephrotoxic drugs or cytotoxic drugs may cause additional renal impairment. It may also reduce potassium concentration; administration with other drugs with this effect may worsen hypokalaemia. Monitor potassium concentration; supplements may be needed. Amikacin: increased risk of nephrotoxicity. Azoles (e.g. fluconazole): possible antagonistic effect; potentially reduced antifungal efficacy. * Ciclosporin: increased risk of nephrotoxicity. * Dexamethasone: increased risk of hypokalaemia (avoid concomitant use unless dexamethasone needed to control reactions). * Digoxin: hypokalaemia caused by amphotericin B increases cardiac toxicity of digoxin. Fluconazole: possible antagonism of effect of amphotericin B. Flucytosine: renal excretion of flucytosine decreased and cellular uptake increased (flucytosine toxicity possibly increased). Furosemide: increased risk of hypokalaemia. Gentamicin: increased risk of nephrotoxicity. Hydrochlorothiazide: increased risk of hypokalaemia. * Hydrocortisone: increased risk of hypokalaemia (avoid concomitant use unless hydrocortisone needed to control reactions). Miconazole: possible antagonism of effects of amphotericin B. Paromomycin: possible increased risk of nephrotoxicity. Pentamidine: possible increased risk of nephrotoxicity. * Prednisolone: increased risk of hypokalaemia (avoid concomitant use unless prednisolone needed to control reactions). Streptomycin: increased risk of nephrotoxicity. Vancomycin: possible increased risk of nephrotoxicity. Notes: Check renal function before starting treatment; monitor renal function and electrolytes (especially potassium, magnesium and sodium) at least three times a week and complete blood picture and hepatic function twice a week during treatment and until stable after treatment stops. Liposomal formulations of amphotericin B are less nephrotoxic than conventional amphotericin B; the few comparative clinical trials between conventional and liposomal formulations appear to show similar efficacy. Conventional (as deoxycholate): use an antihistamine, paracetamol and/or hydrocortisone in patients who have previously experienced acute adverse reactions to prevent or treat infusion reactions. ADMINISTRATION ADVICe (both formulations). Incompatible with sodium chloride solutions; flush existing line with glucose 5% or use a separate line. Do not mix with any other drugs. After initial reconstitution, do not administer without further dilution. Conventional amphotericin B (as deoxycholate) Reduce risk of thrombophlebitis by using large peripheral veins or a central venous catheter, changing venous access sites frequently and infusing over longer periods. Reconstitute as per product instructions including further dilution with glucose 5% to produce a final concentration of 0.1 mg/ml (in fluid restricted children up to 0.4 mg/ml if given via a central line). Initial test dose should be given over 20–30 minutes. To minimize infusion related reactions, infuse the initial treatment dose slowly over 4–6 hours; tolerance to infusion reactions increases with subsequent doses, which may allow a shorter infusion, however, do not give over < 2 hours. Liposomal amphotericin B Reconstitute as per product instructions including filtering through a 5 micron filter and further dilute with glucose 5% to produce a final concentration of 0.2–2 mg/ml. Initial test dose should be given over 10 minutes. Then infuse subsequent doses over 30–60 minutes. WHO Model Formulary for Children 2010 145
    • 6 Anti-infective medicines References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Flucytosine ATC code: J02AX01 Capsule: 250 mg Infusion: 10 mg/ml in 250 ml Keep flucytosine injection at 15–25 °C (forms fluorouracil above 25 °C and can precipitate below 15 °C). Use with extreme caution in patients with impaired renal function. Close monitoring of haematological, renal and hepatic status of all patients is essential. Special Notes: Also known as 5-FC. Indications: Adjunct to amphotericin B (or fluconazole) in cryptococcal meningitis; adjunct to amphotericin B in systemic candidiasis. Precautions: Renal impairment; use with amphotericin B (both nephrotoxic); hepatic impairment; liver and kidney function tests and blood counts required (weekly in renal impairment or in blood disorders); bone marrow depression, myelosuppressive drugs, radiation treatment, patients with AIDS have an increased risk of blood dyscrasias; monotherapy due to emergent resistance. Dose: Adjunct to amphotericin B (or fluconazole) in cryptococcal meningitis; adjunct to amphotericin B in systemic candidiasis. Oral or IV: Neonate 50 mg/kg every 12 hours. Infant or Child 50 mg/kg every 6 hours. In infections due to extremely sensitive organisms, 25–37.5 mg/kg every 6 hours may be sufficient. Treatment does not usually extend beyond 7 days. Continue for at least 4 months in cryptococcal meningitis. Renal impairment: Reduce dose and monitor plasma flucytosine concentration. Mild renal impairment: usual dose every 12 hours. Moderate renal impairment: usual dose every 24 hours. Severe renal impairment: usual dose every 24–48 hours. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Nausea, vomiting, diarrhoea, rashes, thrombocytopenia, photosensitivity. Uncommon Cardiotoxicity, confusion, hallucinations, psychosis, seizures, headache, sedation, vertigo, gastrointestinal haemorrhage, alterations in liver function tests including hepatitis, toxic epidermal necrolysis, peripheral neuropathy. Rare Anaphylaxis, hepatic necrosis, blood disorders including thrombocytopenia, leukopenia and aplastic anaemia. Interactions with other medicines (* indicates severe): Flucytosine depresses the bone marrow; administration with other drugs which also have this effect may increase the risk of myelosuppression. 146 WHO Model Formulary for Children 2010
    • 6.3 Antifungal medicines If it is given with nephrotoxic drugs, its renal excretion may be reduced, increasing the risk of toxicity. Amphotericin B: renal excretion of flucytosine decreased and cellular uptake increased (flucytosine toxicity possibly increased). Cytarabine: plasma flucytosine concentration possibly reduced. Zidovudine: concomitant administration may increase the risk of haematological toxicity. Caution if used together. Notes: Monitoring is essential in renal impairment, when using with amphotericin B, or if there is an increased risk of bone marrow suppression, e.g. in patients with AIDS. Resistance to flucytosine can develop during therapy and sensitivity testing is essential before and during treatment. Take the capsules with food to reduce stomach upset. PLASMA CONCeNTRATION MONITORING For plasma concentration monitoring, blood should be taken shortly before starting the next infusion (or before next dose by mouth). Plasma concentration for optimum response 25–50 mg/l (200–400 micromol/l) and should not exceed 80 mg/l (620 micromol/l). References: American Academy of Pediatrics. Red Book: 2009 report of the committee on infectious diseases. 28th ed. elk Grove Village, American Academy of Pediatrics, 2009. Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. eTG complete. Melbourne, Therapeutic Guidelines Limited, 2009 (http://etg.tg.org.au/ip/, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Jarvis JN et al. Managing cryptococcosis in the immunocompromised host. Current Opinion in Infectious Diseases, 2008, 21(6):596–603. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Potassium iodide ATC code: D01BA Saturated solution Special Notes: Also referred to as saturated solution of potassium iodide or SSKI®. easily confused with potassium iodide and iodine (strong iodide solution, or Lugol’s solution). Indications: Sporotrichosis; subcutaneous phycomycosis. Contraindications: Hypersensitivity to iodides; acute bronchitis or active tuberculosis. Precautions: Not for long-term use; Addison disease; cardiac disease; hyperthyroidism; myotonia congenita; renal impairment. Dose: Sporotrichosis and subcutaneous phycomycosis. Oral: Child all ages initiate at 1 drop three times daily, increasing as tolerated, up to a maximum of 1 drop per kg of body weight or 40–50 drops three times daily, whichever is lowest. Treatment should be continued for at least 4 weeks after resolution or stabilization of lesions. NOTe If signs of iodism occur, suspend treatment temporarily and restart after a few days at lower dosage. These doses assume a solution of 1 g/ml. WHO Model Formulary for Children 2010 147
    • 6 Anti-infective medicines Renal impairment: Use with caution. Hepatic impairment: Dose reduction not necessary. Adverse effects: Common Hypothyroidism, hyperthyroidism, metallic taste, increased salivation, coryza-like symptoms and irritation and swelling of the eyes, lacrimation, conjunctivitis, gastrointestinal disturbances, diarrhoea, skin reactions including acneiform. Uncommon Pulmonary oedema, bronchitis, depression, insomnia, headache, laryngitis, goitre. Rare Pain or inflammation of salivary glands, hypersensitivity reactions, Jod-Basedow phenomenon (iodine-induced thyrotoxicosis). Interactions with other medicines (* indicates severe): Potassium iodide contains potassium and can cause hyperkalaemia. Potassium salts and medicines which may increase serum potassium concentrations should be used with caution. * Ciclosporin: increased risk of hyperkalaemia. * Enalapril: increased risk of severe hyperkalaemia. * Spironolactone: risk of hyperkalaemia. Notes: ADMINISTRATION Give after meals with food or milk. References: Aronson JK, ed. Meyler’s side effects of drugs. 15th ed. Amsterdam, elsevier, 2006. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hynes, Kay. Thyroid blockade with iodine prior to MIBG scan (nuclear medicine procedure) - Lugol’s iodine dosage protocol. Melbourne, Pharmacy Department, Royal Children’s Hospital, Unpublished 2008. Kauffman C et al. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 2007, 45(10):1255–1265 (Medline accessed 16 December 2009). Mcevoy GK, ed. AHFS drug information. Bethesda, American Society of Health-System Pharmacists, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Sweetman SC, ed. Martindale: the complete drug reference. 34th ed. London, Pharmaceutical Press, 2005. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 6.4 Antiviral medicines 6.4.1 Antiherpes medicines Herpes simplex infections Aciclovir is active against herpes viruses but does not eradicate them. It is indicated in children for herpes simplex virus (HSV) infections but is only effective if started early in the course of infection. HSV infections can be primary or reactivation infections, and include superficial infections, genital herpes, eczema herpeticum, herpetic whitlow and eye involvement. HSV encephalitis is a serious, treatable condition that should not be missed. Invasive and disseminated infection can occur in immunocompromised patients. Varicella-zoster infection (chickenpox) Chickenpox in neonates should be treated with parenteral aciclovir to reduce the risk of severe disease. Otherwise, antiviral treatment is generally not required except for immunocompromised patients and those at special risk (e.g. those with severe cardiovascular or respiratory disease or a chronic skin disorder). While most HIV-positive patients with herpes zoster (shingles) experience only one self-limiting disease course, some will suffer repeated episodes. Treatment should be reserved for debilitating disease and when there is a high risk of serious complications, such as in advanced HIV disease. 148 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Aciclovir ATC code: J05AB01 Oral liquid: 40 mg/ml Powder for injection: 250 mg (as sodium salt) in vial Tablet: 200 mg Special Notes: Also referred to as acyclovir. Indications: Treatment and prophylaxis of herpes simplex infections; zoster infections. Precautions: Maintain adequate hydration; renal impairment. Dose: Herpes simplex (non-encephalitis) treatment including genital herpes. Immunocompetent patients. Oral: Child less than 2 years 100 mg five times daily; 2 years and over 200 mg five times daily. Treatment usually for 5 days; longer if new lesions appear during treatment or if healing incomplete. Immunocompromised patients. Oral: Child 1 month–2 years 200 mg five times daily for 7–14 days; 2–12 years 400 mg five times daily for 7–14 days. Disseminated herpes simplex treatment. IV: Neonate to Infant under 3 months 20 mg/kg every 8 hours for 10–14 days (21 days if CNS involvement). Child 3 months–12 years 250 mg/m2 every 8 hours, usually for 5 days. Herpes simplex prophylaxis in immunocompromised patients. Oral: Child less than 2 years 100–200 mg four times daily; 2 years and over 200–400 mg four times daily. Chickenpox treatment (usually only prescribed if immunocompromised). Oral: Child less than 2 years 200 mg four times daily; 2–5 years 400 mg four times daily; over 5 years 800 mg four times daily. Varicella zoster treatment. Immunocompetent patients. IV: Neonate to Infant under 3 months 10–20 mg/kg every 8 hours for at least 7 days. Child 3 months–12 years 250 mg/m2 every 8 hours usually for 5 days. Immunocompromised patients. IV: Neonate to Infant under 3 months 20 mg/kg every 8 hours for at least 7 days. Child 3 months–12 years 500 mg/m2 every 8 hours usually for 5 days. Herpes simplex encephalitis treatment. IV: Child 3 months–12 years 500 mg/m2 every 8 hours usually for 14–21 days. Renal impairment: Intravenous dose reduction required in mild to severe impairment. Oral dose reduction required in moderate to severe impairment. Hepatic impairment: Dose reduction not necessary. WHO Model Formulary for Children 2010 149
    • 6 Anti-infective medicines Adverse effects: Common Nausea, vomiting, diarrhoea, hallucinations (high dose), headache, encephalopathy (reported in 1% patients with IV use), injection site reactions. Uncommon Agitation, vertigo, confusion, dizziness, oedema, renal impairment, arthralgia, sore throat, abdominal pain, constipation, rash, weakness. Rare Coma, seizures, neutropenia, leukopenia, anaemia, thrombocytopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis. Interactions with other medicines (* indicates severe): Ciclosporin: increased risk of nephrotoxicity. Zidovudine: neurotoxicity. Notes: Make sure that you drink plenty of fluids. If you wish, you can disperse tablets in water. Body surface area (m2) = height (cm) x weight (kg) 3600 References: Ashley C, Currie A, eds. The renal drug handbook. 3rd ed. Oxford, Radcliffe Publishing, 2009. Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Klasco RK, ed. Drugdex system. Greenwood Village, Thomson Micromedex, 2010. (http://www.thomsonhc.com, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). 6.4.2 Antiretrovirals Antiretroviral therapy in children Antiretroviral (ART) medicines are essential for the treatment and prevention of HIV infection in children, prevention of mother-to-child transmission (MTCT) and post-exposure prophylaxis. Studies of ART in children demonstrate that similar improvements to those obtained in adults are seen in morbidity, mortality and surrogate markers with many different potent ART regimens. ART in children is aimed at reducing the plasma viral load as much as possible for as long as possible, in order to improve immune function, reduce risk of opportunistic infections and other complications of human immunodeficiency virus (HIV) infection (e.g. encephalopathy and malignancy) and facilitate improved growth, development and quality of life. In all populations, drug therapy should be designed to minimize the risk of toxicity and development of resistance, and maximize long-term compliance. Unique considerations for the use of ART in children include the following: • fewer drug choices than for adults (e.g. efavirenz is not approved for children less than 3 years of age) • limitations of formulations for paediatric patients (e.g. large volumes required [e.g. stavudine liquid], poor palatability [e.g. ritonavir], the need for refrigeration [e.g. lopinavir] and short shelf-life [e.g. didanosine]) • limitations of currently available pharmacokinetic data for children, leading to uncertain dosing regimens for some medications 150 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines • the need for dose adjustment as children grow (to avoid under-dosing and drug resistance) • less data regarding toxicity for children and non-specific clinical manifestations of toxicity in infants • longer potential cumulative treatment duration. Prevention of mother-to-child transmission To prevent the transmission of HIV from mother to baby, WHO promotes a comprehensive approach, which includes the following four components: • primary prevention of HIV infection among women of childbearing age • preventing unintended pregnancies among women living with HIV • preventing HIV transmission from a woman living with HIV to her infant • providing appropriate treatment, care and support to mothers living with HIV and to their children and families. Detailed recommendations for prevention of MTCT of HIV, including the role of ART, can be accessed at the following website: http://www.who.int/hiv/topics/mtct/en/index.html Post-exposure prophylaxis Treatment with antiretroviral drugs may be appropriate following exposure to HIV-contaminated materials and sexual assault. Current WHO guidelines on post-exposure prophylaxis to prevent HIV infection are accessible at the following website: http://www.who.int/hiv/topics/prophylaxis/en/ Fixed-dose drug combinations • Fixed-dose drug combinations, now available in many regions, allow for easier administration of antiretroviral medications based on age or weight bands. They have the advantages of being relatively more affordable, more tolerable for children than multiple tablets, avoiding dosing errors and potentially improving adherence. Lamivudine + Nevirapine + Stavudine ATC code: J05AR07 Tablet: 150 mg + 200 mg + 30 mg Tablet (dispersible): 30 mg + 50 mg + 6 mg; 60 mg + 100 mg + 12 mg ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. WHO Model Formulary for Children 2010 151
    • 6 Anti-infective medicines The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. Special Notes: Also referred to as 3TC+NVP+d4T. Indications: HIV infection (alone as a complete regimen, or in combination with other antiretroviral drugs). Contraindications: NeVIRAPINe Moderate or severe hepatic impairment; post-exposure prophylaxis. Precautions: LAMIVUDINe Pancreatitis (see below); renal impairment; chronic hepatitis B or C; hepatic disease (see below). Pancreatitis If no suitable alternative exists, use with extreme caution in children with advanced HIV infection, previous history of pancreatitis or risk factors for pancreatitis. Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported; caution in children with hepatomegaly, hepatitis (especially hepatitis C treated with interferon alfa and ribavirin), liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. exacerbation of hepatitis in patients with chronic hepatitis B may occur on discontinuation of lamivudine. NeVIRAPINe Hepatic impairment; chronic hepatitis B or C; high CD4 cell count. Hepatic disease Potentially life-threatening hepatotoxicity including fatal fulminant hepatitis reported usually in the first 6 weeks; close monitoring required during first 18 weeks; discontinue permanently if liver abnormalities accompanied by hypersensitivity reaction (rash, fever, arthralgia, myalgia, lymphadenopathy, hepatitis, renal impairment, eosinophilia, granulocytopenia); suspend if severe liver abnormalities but no hypersensitivity reaction; discontinue permanently if significant liver function abnormalities recur, monitor patient closely if mild to moderate liver abnormalities with no hypersensitivity reaction. Rash Rash, usually in first 6 weeks, is most common side-effect; incidence reduced if introduced at low dose and dose increased gradually, monitor closely for skin reactions during first 18 weeks; discontinue permanently if severe rash or if rash accompanied by blistering, oral lesions, conjunctivitis, facial oedema, general malaise or hypersensitivity reactions; if rash mild or moderate, may continue without interruption but dose should not be increased until rash resolves. PATIeNT ADVICe Patients and/or caregivers should be told how to recognize hypersensitivity reactions and advised to discontinue treatment and seek immediate medical attention if symptoms of hepatitis, severe skin reaction or hypersensitivity reactions develop. STAVUDINe Peripheral neuropathy (see below); pancreatitis (see below); chronic hepatitis B or C; hepatic disease (see below); renal impairment. 152 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Peripheral neuropathy Suspend if peripheral neuropathy develops (characterized by persistent numbness, tingling or pain in feet or hands); if symptoms resolve satisfactorily on withdrawal and if stavudine needs to be continued, resume treatment at half previous dose. Pancreatitis Avoid use or use extreme caution in patients with history of pancreatitis. If symptoms of pancreatitis develop or if serum amylase or lipase is raised (even if asymptomatic), suspend treatment until diagnosis of pancreatitis excluded; on return to normal values, re-initiate treatment only if essential (using low dose increased gradually if appropriate). Whenever possible, avoid concomitant treatment with other drugs known to cause pancreatic toxicity (for example, intravenous pentamidine isetionate); monitor closely if concomitant therapy unavoidable. Since significant elevations of triglycerides cause pancreatitis, monitor closely if elevated. Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported. Caution in patients with hepatomegaly, hepatitis, liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. Dose: HIV infection (alone as a complete regimen, or in combination with other antiretroviral drugs). SPeCIAL CONSIDeRATIONS FOR DOSING A lead-in dose of nevirapine, half of the normal daily dosage, is used for 2 weeks to decrease the likelihood of rash incidence. For children < 30 kg, use of 14 day lead-in decreases the incidence of rash. If the child experiences a rash in the lead-in period, then remain on the half dosage until the rash resolves. Wait no longer than 28 days for the rash to resolve then seek an alternative regimen. Contains a fixed dose of nevirapine, therefore cannot be used for nevirapine induction as nevirapine dose escalation is required; use individual components during induction period. See individual drug monographs for dose recommendations. Lamivudine + Nevirapine + Stavudine: recommended dosing based on weight bands Weight range (kg) Target doses Dose (tablets) Lamivudine 4 mg/kg twice daily Nevirapine 160–200 mg/m2 twice daily after 2 week induction dose Stavudine 1 mg/kg twice daily Bottom Top Formulation a.m. p.m. Lamivudine/ nevirapine/ stavudine tablets 3 3.9 30 mg/50 mg/6 mg 1 1 4 4.9 30 mg/50 mg/6 mg 1 1 5 5.9 30 mg/50 mg/6 mg 1 1 6 6.9 30 mg/50 mg/6 mg 2 1 7 7.9 30 mg/50 mg/6 mg 2 1 8 8.9 30 mg/50 mg/6 mg 2 1 9 9.9 30 mg/50 mg/6 mg 2 1 10 10.9 30 mg/50 mg/6 mg 2 2 11 11.9 30 mg/50 mg/6 mg 2 2 12 13.9 30 mg/50 mg/6 mg 2 2 14 16.9 30 mg/50 mg/6 mg 3 2 17 19.9 30 mg/50 mg/6 mg 3 2 20 24.9 30 mg/50 mg/6 mg 3 3 25 29.9 150 mg/200 mg/30 mg 1 1 30 34.9 150 mg/200 mg/30 mg 1 1 WHO Model Formulary for Children 2010 153
    • 6 Anti-infective medicines Renal impairment: LAMIVUDINe Moderate to severe: reduce dose. NeVIRAPINe Mild and moderate: no dosage adjustment required. Severe: use with caution. STAVUDINe Mild: reduce dose to 50%. Moderate: reduce dose to 25%. Hepatic impairment: LAMIVUDINe Dosage adjustment not required; use with caution in patients with decompensated liver disease. See notes in Precautions. NeVIRAPINe Avoid in moderate or severe hepatic impairment. Use with caution in mild and moderate impairment. See notes in Precautions. STAVUDINe Dosage adjustment not required; use with caution in patients with liver disease. See notes in Precautions. Adverse effects: LAMIVUDINe Common Headache, fatigue, nausea, anorexia, diarrhoea, skin rash, abdominal pain, pancreatitis (more commonly reported in children; up to 14%). Uncommon Peripheral neuropathy, anaemia, decreased neutrophil count, increased liver enzymes, fat redistribution (see Lipodystrophy, below), lactic acidosis, severe hepatomegaly with steatosis. NeVIRAPINe Common Rash, nausea, headache, fever. Uncommon Hepatotoxicity (can be severe, life threatening and possibly fatal), vomiting, abdominal pain, fatigue, myalgia, Stevens-Johnson syndrome. Rare Toxic epidermal necrolysis, diarrhoea, angioedema, hypersensitivity reactions, arthralgia, anaemia and granulocytopenia. STAVUDINe Common Headache, gastrointestinal disturbances, skin rashes. Uncommon Peripheral neuropathy, pancreatitis, fat redistribution (see Lipodystrophy, below), lactic acidosis, severe hepatomegaly with steatosis, sleep disorders. Rare Increased liver enzymes, rapidly progressive ascending neuromuscular weakness. LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. Interactions with other medicines (* indicates severe): LAMIVUDINe * Emtricitabine: no information available; manufacturer advises avoid concomitant use. * Interferon alfa: increased risk of hepatic toxicity. * Ribavirin: increased risk of hepatic toxicity. Sulfamethoxazole + trimethoprim: plasma concentration of lamivudine increased (avoid concomitant use of high-dose sulfamethoxazole + trimethoprim). NeVIRAPINe * Contraceptives, oral: accelerated metabolism of estrogens and progestogens (reduced contraceptive effect). Efavirenz: plasma efavirenz concentration reduced. * Fluconazole: increased plasma concentration of nevirapine. Indinavir: nevirapine reduces plasma concentration of indinavir. * Levonorgestrel: accelerated metabolism of levonorgestrel (reduced contraceptive effect). Lopinavir: plasma concentration of lopinavir possibly reduced. * Medroxyprogesterone: accelerated metabolism of medroxyprogesterone (does not apply to injectable medroxyprogesterone acetate for contraception). * Norethisterone: accelerated metabolism of norethisterone (reduced contraceptive effect). * Rifampicin: reduced plasma concentration of nevirapine (avoid concomitant use). Saquinavir: plasma concentration of saquinavir reduced. 154 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines * St John’s wort (Hypericum): reduced plasma concentration of nevirapine (avoid concomitant use). * Voriconazole: increased plasma concentration of nevirapine and reduced concentration of voriconazole. * Warfarin: enhanced or reduced anticoagulant effect. STAVUDINe * Didanosine: increased risk of adverse effects. * Ribavirin: may decrease stavudine levels, also increased risk of fatal and non-fatal lactic acidosis. * Zidovudine: may antagonize effect of stavudine (concomitant use contraindicated). Notes: Can be given without regard to food. Contains a fixed dose of nevirapine, therefore cannot be used for nevirapine induction as dose escalation required. During induction period, give individual drugs separately. Twice daily fixed dose tablet can be started if no rash or liver function test abnormalities present. Tablets should preferably not be split unless scored. References: Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, Forthcoming 2010. Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric antiretroviral drugs: dosing: A report prepared for the WHO working group on paediatric ARV medicines. Geneva, World Health Organization, 2007 (http://www.who.int/hiv/paediatric/external_report_dosing_paediatric_ARVs.pdf, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. WHO 17th expert committee on the selection and use of essential medicines. Unedited draft report of the 17th expert committee on the selection and use of essential medicines. WHO Technical Report Series, 18 May 2009 (http://www.who.int/selection_ medicines/committees/expert/17/WeBuneditedTRS_2009.pdf ). WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). Lamivudine + Nevirapine + Zidovudine ATC code: J05AR05 Tablet: 30 mg + 50 mg + 60 mg; 150 mg + 200 mg + 300 mg ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. WHO Model Formulary for Children 2010 155
    • 6 Anti-infective medicines The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. Special Notes: Also referred to as 3TC+NVP+ZDV. Zidovudine also referred to as AZT. Indications: HIV infection. Contraindications: NeVIRAPINe Severe hepatic impairment; post-exposure prophylaxis. ZIDOVUDINe Abnormally low neutrophil counts or haemoglobin; neonates either with hyperbilirubinaemia requiring treatment other than phototherapy or with raised transaminase; acute porphyria. Precautions: LAMIVUDINe Pancreatitis (see below); renal impairment; chronic hepatitis B or C; hepatic disease (see below). Pancreatitis If no suitable alternative exists, use with extreme caution in children with advanced HIV infection and previous history of pancreatitis or risk factors for pancreatitis. Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported; caution in children with hepatomegaly, hepatitis (especially hepatitis C treated with interferon alfa and ribavirin), liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. exacerbation of hepatitis in patients with chronic hepatitis B may occur on discontinuation of lamivudine. NeVIRAPINe Hepatic impairment; chronic hepatitis B or C; high CD4 cell count. Hepatic disease Potentially life-threatening hepatotoxicity including fatal fulminant hepatitis reported usually in the first 6 weeks; close monitoring required during first 18 weeks; discontinue permanently if liver abnormalities accompanied by hypersensitivity reaction (rash, fever, arthralgia, myalgia, lymphadenopathy, hepatitis, renal impairment, eosinophilia, granulocytopenia); suspend if severe liver abnormalities but no hypersensitivity reaction; discontinue permanently if significant liver function abnormalities recur, monitor patient closely if mild to moderate liver abnormalities with no hypersensitivity reaction. Rash Rash, usually in first 6 weeks, is most common side-effect; incidence reduced if introduced at low dose and dose increased gradually, monitor closely for skin reactions during first 18 weeks; discontinue permanently if severe rash or if rash accompanied by blistering, oral lesions, conjunctivitis, facial oedema, general malaise or hypersensitivity reactions; if rash mild or moderate, may continue without interruption but dose should not be increased until rash resolves. PATIeNT ADVICe Patients and caregivers should be told how to recognize hypersensitivity reactions and advised to discontinue treatment and seek immediate medical attention if symptoms of hepatitis, severe skin reaction or hypersensitivity reactions develop. 156 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines ZIDOVUDINe Haematological toxicity, including vitamin B12 deficiency, anaemia and myelosuppression; renal impairment; chronic hepatitis B or C; hepatic disease (see below). Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported. exercise caution in patients with hepatomegaly, hepatitis, liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if there is any rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. Dose: HIV infection (alone as a complete regimen, or in combination with other antiretroviral drugs). SPeCIAL CONSIDeRATIONS FOR DOSING A lead-in dose of nevirapine, half of the normal daily dosage, is used for 2 weeks to decrease the likelihood of rash incidence. For children < 30 kg, use of 14 day lead-in decreases the incidence of rash. If the child experiences a rash in the lead-in period, then remain on the half dosage until the rash resolves. Wait no longer than 28 days for the rash to resolve then seek an alternative regimen. Contains a fixed dose of nevirapine, therefore cannot be used for nevirapine induction as nevirapine dose escalation required; use individual components during induction period. See individual drug monographs for dose recommendations. Lamivudine + Nevirapine + Zidovudine: recommended dosing based on weight bands Weight range (kg) Target doses Dose (tablets) Lamivudine 4 mg/kg twice daily Nevirapine 160–200 mg/m2 twice daily after 2 week induction dose Zidovudine 180–240 mg/m2 twice daily Bottom Top Formulation a.m. p.m. Lamivudine/ nevirapine/ zidovudine tablets 3 3.9 30 mg/50 mg/60 mg 1 1 4 4.9 30 mg/50 mg/60 mg 1 1 5 5.9 30 mg/50 mg/60 mg 1 1 6 6.9 30 mg/50 mg/60 mg 2 1 7 7.9 30 mg/50 mg/60 mg 2 1 8 8.9 30 mg/50 mg/60 mg 2 1 9 9.9 30 mg/50 mg/60 mg 2 1 10 10.9 30 mg/50 mg/60 mg 2 2 11 11.9 30 mg/50 mg/60 mg 2 2 12 13.9 30 mg/50 mg/60 mg 2 2 14 16.9 30 mg/50 mg/60 mg 3 2 17 19.9 30 mg/50 mg/60 mg 3 2 20 24.9 30 mg/50 mg/60 mg 3 3 25 29.9 150 mg/200 mg/300 mg 1 1 30 34.9 150 mg/200 mg/300 mg 1 1 Renal impairment: LAMIVUDINe Reduce dose in moderate and severe impairment. NeVIRAPINe Mild and moderate: no dosage adjustment required. Severe: use with caution. ZIDOVUDINe Severe: reduce dose. Hepatic impairment: LAMIVUDINe Dosage adjustment not required; use with caution in patients with decompensated liver disease. See notes in Precautions. WHO Model Formulary for Children 2010 157
    • 6 Anti-infective medicines NeVIRAPINe Avoid in moderate and severe hepatic impairment. Use with caution in mild impairment. See notes in Precautions. ZIDOVUDINe Dosage adjustment may be required; accumulation may occur. Use with caution; monitor for haematological toxicities frequently. Adverse effects: LAMIVUDINe Common Headache, fatigue, nausea, anorexia, diarrhoea, skin rash, abdominal pain, pancreatitis (more commonly reported in children; up to 14%). Uncommon Peripheral neuropathy, anaemia, decreased neutrophil count, increased liver enzymes, fat redistribution (see Lipodystrophy, below), lactic acidosis, severe hepatomegaly with steatosis. NeVIRAPINe Common Rash, nausea, headache, fever. Uncommon Hepatotoxicity (can be severe, life threatening and possibly fatal), vomiting, abdominal pain, fatigue, myalgia, including Stevens-Johnson syndrome. Rare Toxic epidermal necrolysis, diarrhoea, angioedema, hypersensitivity reactions, arthralgia, anaemia and granulocytopenia. ZIDOVUDINe Common Haematological toxicity including neutropenia, leukopenia and anaemia, severe headache, malaise, nausea, vomiting, anorexia. Uncommon Myopathy (associated with prolonged use), myositis, liver toxicity, lactic acidosis, severe hepatomegaly with steatosis, fat redistribution (see Lipodystrophy, below), skin and nail pigmentation, neuropathy. LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. Interactions with other medicines (* indicates severe): LAMIVUDINe * Emtricitabine: no information available; manufacturer advises avoid concomitant use. * Interferon alfa: increased risk of hepatic toxicity. * Ribavirin: increased risk of hepatic toxicity. Sulfamethoxazole + trimethoprim: plasma concentration of lamivudine increased (avoid concomitant use of high-dose sulfamethoxazole + trimethoprim). NeVIRAPINe * Contraceptives, oral: accelerated metabolism of estrogens and progestogens (reduced contraceptive effect). Efavirenz: plasma efavirenz concentration reduced. * Fluconazole: increased plasma concentration of nevirapine. Indinavir: nevirapine reduces plasma concentration of indinavir. * Levonorgestrel: accelerated metabolism of levonorgestrel (reduced contraceptive effect). Lopinavir: plasma concentration of lopinavir possibly reduced. * Medroxyprogesterone: accelerated metabolism of medroxyprogesterone (does not apply to injectable medroxyprogesterone acetate for contraception). * Norethisterone: accelerated metabolism of norethisterone (reduced contraceptive effect). * Rifampicin: reduced plasma concentration of nevirapine (avoid concomitant use). Saquinavir: plasma concentration of saquinavir reduced. 158 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines * St John’s wort (Hypericum): reduced plasma concentration of nevirapine (avoid concomitant use). * Voriconazole: increased plasma concentration of nevirapine and reduced concentration of voriconazole. * Warfarin: enhanced or reduced anticoagulant effect. ZIDOVUDINe NOTe Increased risk of toxicity with nephrotoxic and myelosuppressive drugs. Fluconazole: increased plasma concentration of zidovudine (increased risk of toxicity). Ganciclovir: increased risk of haematological toxicity. * Interferon alfa: increased risk of hepatic and haematological toxicity. Phenytoin: plasma phenytoin concentration increased or decreased by zidovudine. Pyrimethamine: increased antifolate effect. * Ribavirin: increased risk of hepatic and haematological toxicity. Rifampicin: avoidance of rifampicin advised by manufacturer of zidovudine. Stavudine: may antagonize effect of stavudine (concomitant use contraindicated). Valproic acid: plasma concentration of zidovudine possibly increased (risk of toxicity). Notes: Can be given without regard to food. Contains a fixed dose of nevirapine, therefore cannot be used for nevirapine induction as dose escalation required. During induction period, give individual drugs separately. Twice daily fixed dose tablet can be started if no rash or liver function test abnormalities present. Tablets should preferably not be split unless scored (to ensure accurate dosing); they may be crushed and mixed with a small amount of food or water and taken immediately. References: Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, Forthcoming 2010. Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric antiretroviral drugs: dosing: A report prepared for the WHO working group on paediatric ARV medicines. Geneva, World Health Organization, 2007 (http://www.who.int/hiv/paediatric/external_report_dosing_paediatric_ARVs.pdf, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. WHO 17th expert committee on the selection and use of essential medicines. Unedited draft report of the 17th expert committee on the selection and use of essential medicines. WHO Technical Report Series, 18 May 2009 (http://www.who.int/selection_ medicines/committees/expert/17/WeBuneditedTRS_2009.pdf ). WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). WHO Model Formulary for Children 2010 159
    • 6 Anti-infective medicines Lamivudine + Zidovudine ATC code: J05AR01 Tablet: 30 mg + 60 mg; 150 mg + 300 mg ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. Special Notes: Also referred to as 3TC + ZDV. Zidovudine also referred to as AZT. Indications: HIV infection (in combination with other antiretroviral drugs). Contraindications: ZIDOVUDINe Abnormally low neutrophil counts or haemoglobin; neonates either with hyperbilirubinaemia requiring treatment other than phototherapy or with raised transaminase; acute porphyria. Precautions: LAMIVUDINe Pancreatitis (see below); renal impairment; chronic hepatitis B or C; hepatic disease (see below). Pancreatitis If no suitable alternative exists, use with extreme caution in children with advanced HIV infection and a previous history of pancreatitis or risk factors for pancreatitis. Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported; caution in children with hepatomegaly, hepatitis (especially hepatitis C treated with interferon alfa and ribavirin), liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. exacerbation of hepatitis in patients with chronic hepatitis B may occur on discontinuation of lamivudine. ZIDOVUDINe Haematological toxicity including vitamin B12 deficiency, anaemia and myelosuppression; renal impairment; chronic hepatitis B or C; hepatic disease (see below). Hepatic disease Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported. exercise caution in patients with hepatomegaly, hepatitis, liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if there is any rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. 160 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Dose: HIV infection (alone as a complete regimen, or in combination with other antiretroviral drugs). Lamivudine + Zidovudine: recommended dosing based on weight bands Weight range (kg) Target doses Dose (tablets) Lamivudine 4 mg/kg twice daily Zidovudine 180–240 mg/m2 twice daily Bottom Top Formulation a.m. p.m. Lamivudine/zidovudine tablets 3 3.9 30 mg/60 mg 1 1 4 4.9 30 mg/60 mg 1 1 5 5.9 30 mg/60 mg 1 1 6 6.9 30 mg/60 mg 2 1 7 7.9 30 mg/60 mg 2 1 8 8.9 30 mg/60 mg 2 1 9 9.9 30 mg/60 mg 2 1 10 10.9 30 mg/60 mg 2 2 11 11.9 30 mg/60 mg 2 2 12 13.9 30 mg/60 mg 2 2 14 16.9 30 mg/60 mg 3 2 17 19.9 30 mg/60 mg 3 2 20 24.9 30 mg/60 mg 3 3 25 29.9 150 mg/300 mg 1 1 30 34.9 150 mg/300 mg 1 1 Renal impairment: LAMIVUDINe Moderate or severe: reduce dose. ZIDOVUDINe Severe: reduce dose. Hepatic impairment: LAMIVUDINe Dosage adjustment not required; use with caution in patients with decompensated liver disease. See notes in Precautions. ZIDOVUDINe Dosage adjustment may be required; accumulation may occur. Use with caution; monitor for haematological toxicities frequently. Adverse effects: LAMIVUDINe Common Headache, fatigue, nausea, anorexia, diarrhoea, skin rash, abdominal pain, pancreatitis (more commonly reported in children; up to 14%). Uncommon Peripheral neuropathy, anaemia, decreased neutrophil count, increased liver enzymes, fat redistribution (see Lipodystrophy below), lactic acidosis, severe hepatomegaly with steatosis. ZIDOVUDINe Common Haematological toxicity including neutropenia, leukopenia and anaemia, severe headache, malaise, nausea, vomiting, anorexia. Uncommon Myopathy (associated with prolonged use), myositis, liver toxicity, lactic acidosis, severe hepatomegaly with steatosis, fat redistribution (see Lipodystrophy below), skin and nail pigmentation, neuropathy. LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. Interactions with other medicines (* indicates severe): LAMIVUDINe * Emtricitabine: no information available; manufacturer advises to avoid concomitant use. * Interferon alfa: increased risk of hepatic toxicity. WHO Model Formulary for Children 2010 161
    • 6 Anti-infective medicines * Ribavirin: increased risk of hepatic toxicity. Sulfamethoxazole + trimethoprim: plasma concentration of lamivudine increased (avoid concomitant use of high dose sulfamethoxazole + trimethoprim). ZIDOVUDINe NOTe Increased risk of toxicity with nephrotoxic and myelosuppressive drugs. Fluconazole: increased plasma concentration of zidovudine (increased risk of toxicity). Ganciclovir: increased risk of haematological toxicity. * Interferon alfa: increased risk of hepatic and haematological toxicity. Phenytoin: plasma phenytoin concentration increased or decreased by zidovudine. Pyrimethamine: increased antifolate effect. * Ribavirin: increased risk of hepatic and haematological toxicity. Rifampicin: avoidance of rifampicin advised by manufacturer of zidovudine. Stavudine: may inhibit effect of stavudine (avoid concomitant use). Valproic acid: plasma concentration of zidovudine possibly increased (risk of toxicity). Notes: No food restrictions apply. Tablets should not be split unless they are scored. Tablets can be crushed and mixed with a small amount of water or food and taken immediately. References: Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, Forthcoming 2010. Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf, accessed 10 February 2010). Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Paediatric antiretroviral drugs: dosing: A report prepared for the WHO working group on paediatric ARV medicines. Geneva, World Health Organization, 2007 (http://www.who.int/hiv/paediatric/external_report_dosing_paediatric_ARVs.pdf, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. WHO 17th expert committee on the selection and use of essential medicines. Unedited draft report of the 17th expert committee on the selection and use of essential medicines. WHO Technical Report Series, 18 May 2009 (http://www.who.int/selection_ medicines/committees/expert/17/WeBuneditedTRS_2009.pdf ). WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). 162 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines 6.4.2.1 Nucleoside/nucleotide reverse transcriptase inhibitors Abacavir ATC code: J05AF06 Oral liquid: 20 mg (as sulfate)/ml Tablet: 300 mg (as sulfate) Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir: approximately 5% of adults and children (rate varies by race/ethnicity) receiving abacavir develop a potentially fatal hypersensitivity reaction. ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases, the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. Special Notes: Also referred to as ABC. Indications: HIV infection, in combination with other antiretroviral drugs. Contraindications: Severe renal impairment; severe hepatic impairment; previous hypersensitivity reaction to abacavir. Precautions: Chronic hepatitis B or C; hepatic impairment; renal impairment. HyPeRSeNSITIVITy ReACTIONS Life-threatening hypersensitivity reactions characterized by fever or rash and possibly nausea, vomiting, diarrhoea, abdominal pain, dyspnoea, cough, lethargy, malaise, headache and myalgia, less frequently by mouth ulceration, oedema, hypotension, sore throat, adult respiratory distress syndrome, paraesthesia, arthralgia, conjunctivitis, lymphadenopathy, lymphocytopenia, renal failure and anaphylaxis (hypersensitivity reactions presenting as sore throat, influenza-like illness, cough and breathlessness identified); and rarely by myolysis. Laboratory abnormalities may include raised liver enzymes (see below) and creatine kinase. Symptoms usually appear in the first 6 weeks, but may occur at any time; monitor patients for symptoms every 2 weeks for 2 months; discontinue immediately if any symptom of hypersensitivity develops and WHO Model Formulary for Children 2010 163
    • 6 Anti-infective medicines do not rechallenge (risk of more severe hypersensitivity reaction); discontinue if hypersensitivity cannot be ruled out, even when other diagnoses possible (if rechallenge necessary, it must be carried out in hospital setting). If abacavir is stopped for any reason other than hypersensitivity, exclude hypersensitivity reaction as the cause, and rechallenge only if medical assistance is readily available; care needed with concomitant use of drugs which cause skin toxicity. Studies have shown an association between abacavir hypersensitivity and a specific HLA genotype (HLA-B*5701). This genetic screening for HLA-B*5701 is recommended prior to initiation of abacavir based therapy. The incidence of abacavir hypersensitivity reaction is lower in the non-Caucasian population. PATIeNT ADVICe Patients and caregivers should be told the importance of regular dosing (intermittent therapy may increase sensitization), how to recognize signs of hypersensitivity, and advised to seek immediate medical attention if symptoms develop or before restarting treatment. HePATIC DISeASe Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis have been reported. Caution in patients with hepatomegaly, hepatitis, liver enzyme abnormalities, or risk factors for liver disease and hepatic steatosis (including alcohol abuse); discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. Dose: HIV infection, in combination with other antiretroviral drugs. Oral: Infant or Child 8 mg/kg/dose given twice daily, maximum 300 mg twice daily. Simplified dosing tables based on weight bands are designed around 60 mg tablets (not on the 2nd WHO Model List of essential Medicines for Children). Abacavir: recommended dosing based on weight bands using 60 mg and 300 mg tablets Weight range (kg) Target dose Dose (tablets) < 16 years or < 37.5 kg: 8 mg/kg/dose given twice daily Maximum dose > 16 years or ≥ 37.5 kg: 300 mg/dose given twice daily Bottom Top Formulation a.m. p.m. 3 3.9 60 mg tablet 1 1 4 4.9 60 mg tablet 1 1 5 5.9 60 mg tablet 1 1 6 6.9 60 mg tablet 2 1 7 7.9 60 mg tablet 2 1 8 8.9 60 mg tablet 2 1 9 9.9 60 mg tablet 2 1 10 10.9 60 mg tablet 2 2 11 11.9 60 mg tablet 2 2 12 13.9 60 mg tablet 2 2 14 16.9 60 mg tablet 3 2 17 19.9 60 mg tablet 3 2 20 24.9 60 mg tablet 3 3 25 29.9 300 mg tablet 1 1 30 34.9 300 mg tablet 1 1 164 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Abacavir: recommended dosing based on weight bands using oral liquid and 300 mg tablets Weight range Target dose Dose (kg) < 16 years or < 37.5 kg: 8 mg/kg/dose given twice daily (ml or tablets) Maximum dose > 16 years or ≥ 37.5 kg: 300 mg/dose given twice daily Bottom Top Formulation a.m. p.m. 3 3.9 20 mg/ml syrup 3 ml 3 ml 4 4.9 20 mg/ml syrup 3 ml 3 ml 5 5.9 20 mg/ml syrup 3 ml 3 ml 6 6.9 20 mg/ml syrup 4 ml 4 ml 7 7.9 20 mg/ml syrup 4 ml 4 ml 8 8.9 20 mg/ml syrup 4 ml 4 ml 9 9.9 20 mg/ml syrup 4 ml 4 ml 10 10.9 20 mg/ml syrup 6 ml 6 ml 11 11.9 20 mg/ml syrup 6 ml 6 ml 12 13.9 20 mg/ml syrup 6 ml 6 ml 14 16.9 300 mg tablet 0.5 0.5 17 19.9 300 mg tablet 0.5 0.5 20 24.9 300 mg tablet 1 0.5 25 29.9 300 mg tablet 1 1 30 34.9 300 mg tablet 1 1 Renal impairment: Severe: avoid. Hepatic impairment: Moderate: avoid unless essential. Severe: avoid. Adverse effects: Common Nausea, vomiting, fever, headache, diarrhoea, rash, anorexia, fatigue. Uncommon Lactic acidosis, severe hepatomegaly with steatosis, pancreatitis, hypersensitivity, lipodystrophy (see below). Rare Increased liver enzymes, elevated blood glucose, elevated triglycerides, possible increased risk of myocardial infarction. LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. Interactions with other medicines (* indicates severe): Methadone: plasma concentration of methadone possibly reduced. Phenobarbital: plasma concentration of abacavir possibly reduced. Phenytoin: plasma concentration of abacavir possibly reduced. Rifampicin: plasma concentration of abacavir possibly reduced. Notes: Parents and carers must be warned about potential hypersensitivity reaction. Abacavir should be stopped permanently if hypersensitivity reaction occurs. Can be given without regard to food. Store oral solution at room temperature (20–25 ºC); may be refrigerated. Tablets may be crushed with a small amount of water or food and administered immediately. WHO Model Formulary for Children 2010 165
    • 6 Anti-infective medicines References: Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric antiretroviral drugs: dosing: A report prepared for the WHO working group on paediatric ARV medicines. Geneva, World Health Organization, 2007 (http://www.who.int/hiv/paediatric/external_report_dosing_paediatric_ARVs.pdf, accessed 10 February 2010). Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. Rossi S, ed. Australian medicines handbook. Adelaide, Australian Medicines Handbook, 2009. Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). Didanosine ATC code: J05AF02 Buffered powder for oral liquid: 100 mg; 167 mg; 250 mg packets Capsule (unbuffered enteric coated): 125 mg; 200 mg; 250 mg; 400 mg Tablet (buffered chewable, dispersible): 25 mg; 50 mg; 100 mg; 150 mg; 200 mg Fatal and non-fatal pancreatitis have been reported during therapy. ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. 166 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Special Notes: Also referred to as ddI. Didanosine is usually reserved for second-line regimens. NOTe Antacids in formulation may affect absorption of other drugs; see interactions. Indications: HIV infection, in combination with at least two other antiretroviral drugs. Precautions: Pancreatitis; peripheral neuropathy; hyperuricaemia; lactic acidosis or severe hepatomegaly with steatosis; chronic hepatitis B or C; retinal or optic nerve changes; renal impairment; hepatic impairment. PANCReATITIS Avoid use or use extreme caution in patients with history of pancreatitis. If symptoms of pancreatitis develop or if serum amylase or lipase is raised (even if asymptomatic), suspend treatment until diagnosis of pancreatitis excluded; on return to normal values, re-initiate treatment only if essential (using low dose increased gradually if appropriate). Whenever possible, avoid concomitant treatment with other drugs known to cause pancreatic toxicity (for example intravenous pentamidine isetionate, stavudine and hydroxyurea); monitor closely if concomitant therapy unavoidable. Since significant elevations of triglycerides cause pancreatitis, monitor closely if elevated. PeRIPHeRAL NeUROPATHy Dose related, especially in advanced HIV infection. Suspend treatment; a reduced dose may be tolerated when symptoms resolve. Please note that giving a lower dose may result in suboptimal therapy and an increased risk of treatment failure and the development of resistant mutations; it may be advisable to change to another drug at full dose. HyPeRURICAeMIA Suspend treatment if significant elevation occurs. HePATIC DISeASe Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported; exercise caution in patients with hepatomegaly, hepatitis, liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. ReTINAL OR OPTIC NeRVe CHANGeS Dilated retinal examinations recommended (especially in children) every 6 months, or if visual changes occur. Asymptomatic peripheral retinal depigmentation in < 5% of children can also occur. Not associated with vision loss and reverses when treatment is stopped. Dose: HIV infection, in combination with at least two other antiretroviral drugs. Oral: Infant under 3 months 50 mg/m2/dose twice daily. Infant over 3 months or Child 90–120 mg/m2/dose twice daily (maximum 200 mg/dose twice daily or 400 mg once daily). Simplified dosing tables based on weight bands are designed around the 25 mg tablets. WHO Model Formulary for Children 2010 167
    • 6 Anti-infective medicines Didanosine: recommended dosing based on weight bands using 25 mg tablets Weight range Target dose Dose (kg) (tablets) < 3 months: 50 mg/m2/dose twice daily 3 months to < 13 years: 90–120 mg/m2/dose twice daily Maximum dose (≥ 13 years or > 60 kg): 200 mg/dose twice daily or 400 mg once daily Bottom Top Formulation a.m. p.m. 3 3.9 25 mg tablet NR NR 4 4.9 25 mg tablet NR NR 5 5.9 25 mg tablet 2 2 6 6.9 25 mg tablet 3 2 7 7.9 25 mg tablet 3 2 8 8.9 25 mg tablet 3 2 9 9.9 25 mg tablet 3 2 10 10.9 25 mg tablet 3 3 11 11.9 25 mg tablet 3 3 12 13.9 25 mg tablet 3 3 14 16.9 25 mg tablet 4 3 17 19.9 25 mg tablet 4 3 20 24.9 25 mg tablet 4 4 25 29.9 25 mg tablet 5 5 30 34.9 25 mg tablet 5 5 Didanosine: recommended dosing based on weight bands using oral suspension and 25 mg tablets Weight range Target dose Dose (kg) (ml or tablets) < 3 months: 50 mg/m2/dose twice daily 3 months to < 13 years: 90–120 mg/m2/dose twice daily Maximum dose (≥ 13 years or > 60 kg): 200 mg/dose twice daily or 400 mg once daily Bottom Top Formulation a.m. p.m. 3 3.9 10 mg/ml suspension 3 ml 3 ml 4 4.9 10 mg/ml suspension 3 ml 3 ml 5 5.9 10 mg/ml suspension 3 ml 3 ml 6 6.9 10 mg/ml suspension 5 ml 5 ml 7 7.9 10 mg/ml suspension 5 ml 5 ml 8 8.9 10 mg/ml suspension 5 ml 5 ml 9 9.9 10 mg/ml suspension 5 ml 5 ml 10 10.9 10 mg/ml suspension 6 ml 6 ml 11 11.9 10 mg/ml suspension 6 ml 6 ml 12 13.9 10 mg/ml suspension 6 ml 6 ml 14 16.9 25 mg tablet 4 3 17 19.9 25 mg tablet 4 3 20 24.9 25 mg tablet 4 4 25 29.9 25 mg tablet 5 5 30 34.9 25 mg tablet 5 5 168 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Renal impairment: Reduce dose in all degrees of impairment; consult product information for individual preparations for further specific dosing information. Hepatic impairment: No dose adjustment recommended. Possible increased risk of toxicity in patients with hepatic impairment; monitor for toxicity. Adverse effects: Common Diarrhoea (sometimes severe, may be related to the antacid present in the preparation), abdominal pain, nausea, vomiting. Uncommon Peripheral neuropathy, electrolyte abnormalities, hyperuricaemia, lactic acidosis, severe hepatomegaly with steatosis, pancreatitis, increased liver enzymes, retinal depigmentation, retinal changes, optic neuritis, hepatic toxicity, hepatic failure, lipodystrophy (see below). LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. Interactions with other medicines (* indicates severe): * Allopurinol: possibly increased plasma concentration of didanosine. * Hydroxyurea: increased risk of adverse effects. Avoid concurrent use if possible. * Ribavirin: increased risk of toxicity, hepatic reactions, peripheral neuropathy and pancreatitis. * Ritonavir: simultaneous administration can inactivate both drugs. Give didanosine 1 hour before or 2 hours after ritonavir. * Stavudine: increased risk of adverse effects. Avoid concurrent use if possible. * Tenofovir: plasma concentration of didanosine increased (increased risk of toxicity; avoid concomitant use). Notes: Best given on an empty stomach 30 minutes before or at least 2 hours after a meal. Didanosine is degraded rapidly unless given as an enteric formulation or combined with buffering agents or antacids. In children, this degradation effect may be less marked and didanosine may not have to be administered on an empty stomach. ORAL SUSPeNSION Is not easy to use and should be avoided if possible; should be kept refrigerated; stable for 30 days; must be well shaken. TABLeTS At least two tablets of appropriate strength must be used at any one time for adequate buffering (e.g. if the child’s dose is 50 mg, administer two 25 mg tablets instead of one 50 mg tablet); didanosine tablets should be chewed, crushed or dispersed in water or clear juice before they are taken; tablets should not be swallowed whole. eNTeRIC-COATeD BeADLeTS IN CAPSULeS Can be opened and sprinkled on a small amount of food, but this may decrease the area under the curve; do not crush or chew beadlets. References: Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/WHOpaediatric. pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. WHO expert committee on the selection and use of essential medicines. The selection and use of essential medicines: report of the WHO expert committee, October 2007 (including the model list of essential medicines for children). WHO Technical Report Series, 2008, 950 (http://www.who.int/medicines/publications/essentialmeds_committeereports/TRS_950.pdf ). Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). WHO Model Formulary for Children 2010 169
    • 6 Anti-infective medicines Emtricitabine ATC code: J05AF09 Capsule: 200 mg Oral liquid: 10 mg/ml ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. Special Notes: Also referred to as FTC. emtricitabine is an acceptable alternative to lamivudine, based on knowledge of the pharmacology, the resistance patterns and clinical trials of antiretrovirals. WHO age/weight restriction: > 3 months. Indications: HIV infection, in combination with at least two other antiretroviral drugs. Contraindications: Avoid concomitant use with lamivudine. Precautions: Renal impairment; hepatic disease. HePATIC DISeASe Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported. exercise caution in patients with hepatomegaly, hepatitis (especially hepatitis C treated with interferon alfa and ribavirin), liver enzyme abnormalities or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. exacerbation of hepatitis in patients with chronic hepatitis B may occur on discontinuation of emtricitabine; monitoring required. Dose: NOTe Oral liquid and capsules are not bioequivalent. 240 mg oral solution ≡ 200 mg capsule; where appropriate, capsules may be used instead of oral solution; oral solution contains propylene glycol as an excipient. HIV infection, in combination with other antiretroviral drugs. Oral: Child over 3 months 6 mg/kg (maximum 200 mg) daily. Renal impairment: Mild or worse impairment: reduce dose or increase dosing interval. Consult product literature. Hepatic impairment: Dosage adjustment not required; use with caution in patients with liver disease. See notes in Precautions. Adverse effects: Common Diarrhoea, nausea, rash (may be higher in African Americans; up to 32% incidence reported), hyperpigmentation of palms and/or soles (more common in children, females and non-Caucasian people). Uncommon Neutropenia, lactic acidosis, severe hepatomegaly with steatosis, lipodystrophy (see below). LIPODySTROPHy Lipodystrophy has been observed in patients taking antiretroviral agents, but a direct causal relationship has not been established. 170 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Interactions with other medicines (* indicates severe): * Ganciclovir: possible increased toxicity of emtricitabine. Lamivudine: avoid concomitant use. * Ribavirin: possible increased toxicity of emtricitabine. * Valganciclovir: possible increased toxicity of emtricitabine. Notes: Can be given without regard to food. Oral solution should be refrigerated. Can be kept at room temperature up to 25 °C if used within 3 months. References: Antiretroviral therapy of HIV infection in infants and children: towards universal access: Recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf, accessed 10 February 2010). Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009. PeNTA Steering Committee. PeNTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Medicine, 2009, 10(10):591–613. Working group on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 23 February 2009:1–139 (http://aidsinfo.nih.gov/contentfiles/pediatricguidelines.pdf, accessed 10 February 2010). Lamivudine ATC code: J05AF05 Oral liquid: 10 mg/ml Tablet: 150 mg ANTIReTROVIRAL DOSING The doses of antiretroviral drugs included in this formulary are based on the WHO guidelines for treatment of paediatric HIV (Antiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach). At the time of printing, these guidelines were under review. Prescribers are encouraged to consult the latest guidelines as they are continually updated as further data or newer formulations become available. The dosing guidance for antiretroviral drugs provided in this formulary has been simplified and includes weight-based tables, as the calculation and administration of exact doses based on body surface area may be impractical in resource-limited settings. The target doses for each drug are included in the tables; however in many cases the dose achieved for a particular patient weight may be significantly higher or slightly lower than the target dose. Decisions about dosing were based upon manufacturer’s information, the antiretroviral drug formulation choices, available data from clinical studies, and expert paediatric pharmacology consultation, and were directed towards what could be considered the “optimal” dose for a particular weight band, given the limitations imposed by currently available drug formulations and the public health advantages of simplified dosing tables. Situations that are frequently encountered in resource-limited settings, including the possible lack of refrigeration and the lack of syrup or liquid forms for small children are taken into consideration. Some of the formulations used to create these simplified dosing guidelines are not included on the 2nd WHO Model List of essential Medicines for Children but may be available locally. Prescribers are urged to consider if the dosing guidelines are appropriate for adoption given the antiretroviral drugs and formulations available locally. WHO Model Formulary for Children 2010 171
    • 6 Anti-infective medicines Special Notes: Also referred to as 3TC. Indications: HIV infection, in combination with at least two other antiretroviral drugs. Precautions: Pancreatitis (see below); renal impairment; chronic hepatitis B or C; hepatic disease (see below). PANCReATITIS If no suitable alternative exists, use with extreme caution in children with advanced HIV infection, previous history of pancreatitis or risk factors for pancreatitis. HePATIC DISeASe Potentially life-threatening lactic acidosis and severe hepatomegaly with steatosis reported; caution in children with hepatomegaly, hepatitis (especially hepatitis C treated with interferon alfa and ribavirin), liver enzyme abnormalities, or risk factors for liver disease and hepatic steatosis; discontinue if rapid deterioration in liver function tests, symptomatic hyperlactataemia, progressive hepatomegaly or lactic acidosis. exacerbation of hepatitis in patients with chronic hepatitis B may occur on discontinuation of lamivudine. Dose: HIV infection, in combination with other antiretroviral drugs. Oral: Neonate 2 mg/kg/dose given twice daily. Infant or Child 4 mg/kg/dose given twice daily, maximum 150 mg twice daily. Simplified dosing tables based on weight bands are designed around 30 mg tablets (not on the 2nd WHO Model List of essential Medicines for Children). Lamivudine: recommended dosing based on weight bands using 30 mg and 150 mg tablets Weight range Target dose Dose (kg) Infant or Child: (tablets) 4 mg/kg twice daily to a maximum of 150 mg twice daily Bottom Top Formulation a.m. p.m. 3 3.9 30 mg tablet 1 1 4 4.9 30 mg tablet 1 1 5 5.9 30 mg tablet 1 1 6 6.9 30 mg tablet 2 1 7 7.9 30 mg tablet 2 1 8 8.9 30 mg tablet 2 1 9 9.9 30 mg tablet 2 1 10 10.9 30 mg tablet 2 2 11 11.9 30 mg tablet 2 2 12 13.9 30 mg tablet 2 2 14 16.9 30 mg tablet 3 2 17 19.9 30 mg tablet 3 2 20 24.9 30 mg tablet 3 3 25 29.9 150 mg tablet 1 1 30 34.9 150 mg tablet 1 1 172 WHO Model Formulary for Children 2010
    • 6.4 Antiviral medicines Lamivudine: recommended dosing based on weight bands using the oral liquid and 150 mg tablets Weight range Target dose Dose (kg) Infant or Child: (ml or tablets) 4 mg/kg twice daily to a maximum of 150 mg twice daily Bottom Top Formulation a.m. p.m. 3 3.9 10 mg/ml solution 3 ml 3 ml 4 4.9 10 mg/ml solution 3 ml 3 ml 5 5.9 10 mg/ml solution 3 ml 3 ml 6 6.9 10 mg/ml solution 4 ml 4 ml 7 7.9 10 mg/ml solution 4 ml 4 ml 8 8.9 10 mg/ml solution 4 ml 4 ml 9 9.9 10 mg/ml solution 4 ml 4 ml 10 10.9 10 mg/ml solution 6 ml 6 ml 11 11.9 10 mg/ml solution 6 ml 6 ml 12 13.9 10 mg/ml solution 6 ml 6 ml 14 16.9 150 mg tablet 0.5 0.5 17 19.9 150 mg tablet 0.5 0.5 20 24.9 150 mg tablet 1 0.5 25 29.9 150 mg tablet 1 1 30 34.9 150 mg tablet 1 1 Renal impairment: Moderate to severe: reduce dose. Hepatic impairment: Dosage adjustment not required; use with caution in patients with decompensated liver disease. See notes in Precautions. Adverse effects: Common Headache, fatigue, nausea, anorexia, diarrhoea, skin rash, abdominal pain, pancreatitis (more commonly reported in children; up to 14%). Uncommon Peripheral neuropathy, anaemia, decreased neutrophil count, increased liver enzymes, fat redistribution (see Lipodyst